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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Anatomy and embryology 202 (2000), S. 247-255 
    ISSN: 1432-0568
    Keywords: Key words Enteric neurons ; Interstitial cells of Cajal ; Smooth muscle cells ; Guinea-pig ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Tachykinin receptors NK1r, NK2r and NK3r bind tachykinins with different affinities and share pharmacological and molecular differences among animal species. NK1r, NK2r, NK3r and tachykinin (SP/NKA) distribution was studied by immunohistochemistry in the ileum of mouse since no data are available for this species. The results were then compared to those obtained in the rat and guinea pig either by us or by others to ascertain interspecies similarities and/or differences. NK1r- and NK3r-immunoreactivity (IR) were detected in neurons and NK1r-IR in the interstitial cells of Cajal at the deep muscular plexus. At variance with rat and guinea pig, NK1r-IR was also found in the myoid cells of the villi, while NK2r-IR was never detected in nerve varicosities. This latter datum suggests that the NK2r does not play a presynaptic role in the mouse. Unexpectedly, a high NK2r-IR and the presence of NK3r-IR were observed at the inner portion of the circular muscle layer in the mouse as well as in the rat and guinea pig, demonstrating a subregional distribution of these receptors. Tachykinin distribution did not show noticeable species-related differences. The present findings show species-related differences in the tachykinin receptor distribution that might be related to a different tachykinin controlof intestinal motility.
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  • 2
    ISSN: 1432-0568
    Keywords: Key words Nerve repair ; Nerve fiber regeneration ; Sciatic nerve ; Muscle-vein-combined graft ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Clinical data have shown that a vein segment filled with fresh skeletal muscle can be considered a good autologous grafting conduit for the repair of peripheral nerve lesions. In this study, the long-term morphological organization of rat sciatic nerve fibers regenerated along a muscle-vein-combined graft conduit is further analysed by light and electron microscopy. Regenerated nerve fibers were organized into fascicles of various sizes that were clearly delimited by perineurial-like shells made by long and thin cytoplasmic processes of perineurial-like bipolar cells and by densely packed collagen fibrils. Grafted skeletal muscle fibers were still detectable among nerve fiber fascicles. However, in spite of the persistence of skeletal muscle along the graft, regenerated nerve fibers showed a good morphological pattern of regeneration, providing further evidence that the muscle-vein-combined grafting technique represents an effective surgical alternative to the classical fresh nerve autograft for the repair of peripheral nerve defects.
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  • 3
    ISSN: 1432-0568
    Keywords: Key words GABAB receptor ; CNS ; Dorsal root ganglia ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The anatomical distribution of the GABAB receptor (GBR) splice variants GBR1a and 1b in the CNS has not previously been studied. In the present study, distribution of the splice variants was mapped using immunohistochemistry. Polyclonal antibodies against splice variant unique epitopes were raised in rabbits. Affinity purified antibodies were used according to routine immunohistochemical procedures in sections from the rat CNS or dorsal root ganglia (DRG). The staining intensity was high in the cerebral cortex but lower in basal ganglia and the hippocampus. In the cerebellum, there was a marked difference in the distribution of GBR1a- and 1b-like immunoreactivity (LI). GBR1a-LI was preferentially localised in the granule cell layer whilst GBR1b-LI was mostly found in Purkinje cells and in the molecular layer. Cell bodies of the deep cerebellar nuclei stained for the GBR1a antibody while terminals surrounding the cell bodies were strongly labelled with the GBR1b antibody. A similar pre- vs postsynaptic pattern was seen in several nuclei ventral or caudal to the cerebellum (e.g. the cochlear nucleus, the facial nucleus, the spinal cord) but not in regions rostral to the cerebellum. In the spinal cord, strong labelling for both antibodies was seen in the dorsal horn. The GBR1b but not the GBR1a antibody stained tanycytes in the epithelium of the 3rd ventricle and in the central canal at the brain stem level. DRG neurons were positive for both the GBR1a and 1b antibody, but the former stained the cells much more intensely. Satellite cells were labelled with the GBR1b antibody. The most important aspect of these findings is that in some nuclei, GBR1b may mediate inhibition of transmitter release while in the same regions, GBR1a may mediate postsynaptic inhibition. Further, the observations support previous findings that GBR1b is the predominant splice variant in Purkinje cells.
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  • 4
    ISSN: 1432-0533
    Keywords: Key words Hypothermia ; Immunohistochemistry ; Microtubule-associated protein 2 (MAP2) ; Rat ; Spinal cord injury
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Systemic hypothermia has been shown to exert neuroprotective effects in experimental ischemic CNS models caused by vascular occlusions. The present study addresses the question as to whether systemic hypothermia has similar neuroprotective qualities following severe spinal cord compression trauma using microtubule-associated protein 2 (MAP2) immunohistochemistry combined with the avidin-biotin-peroxidase complex method as marker to identify neuronal and dendritic lesions. Fifteen rats were randomized into three equally sized groups. One group sustained thoracic laminectomy, the others severe spinal cord compression trauma of the T8-9 segment. The control group contained laminectomized animals submitted to a hypothermic procedure in which the esophageal temperature was reduced from 38 °C to 30 °C. The two trauma groups were either submitted to the same hypothermic procedure or kept normothermic during the corresponding time. All animals were sacrificed 24 h following the surgical procedure. The MAP2 immunostaining in the normothermic trauma group indicated marked reductions in MAP2 antigen in the cranial and caudal peri-injury zones (T7 and T10, respectively). This reduction was much less pronounced in the hypothermic trauma group. In fact, the MAP2 antigen was present in almost equally sized areas in both the hypothermic groups independent of previous laminectomy alone or the addition of trauma. Our study thus indicates that hypothermia has a neuroprotective effect on dendrites of rat spinal cords subjected to compression trauma.
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Acta neuropathologica 100 (2000), S. 75-81 
    ISSN: 1432-0533
    Keywords: Key words Fas ; Fas ligand ; Rat ; Spinal cord ; Trauma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This immunohistochemical study evaluated Fas and Fas ligand (FasL) in the rat nervous system and their changes in the spinal cord subjected to compression. Normal spinal cord showed a low level of Fas and FasL immunoreactivity in the white matter except in the corticospinal tracts. Fas and FasL immunoreactivity seemed to be located in axons and their myelin sheaths. Other regions of the nervous system did not show immunoreactivity to Fas and FasL. Moderate and severe compression injury of the spinal cord resulted in a reduction of Fas and FasL immunoreactivity in the white matter of injured T8–9 segments at 4 h and a complete loss at 1 day after trauma. This was seen even in the remaining white matter. In contrast, increased immunoreactivity to Fas and FasL was present in the cranial T7, caudal T10 (moderate injury) and T12 (severe injury) segments at day 4 with most intense staining were seen at day 9 after trauma. Increased Fas and FasL immunoreactivity may have pathophysiological implications for the development of secondary injuries after trauma to the spinal cord. Fas-FasL interactions may for instance be involved in apoptosis of oligodendrocytes which occurs as a delayed phenomenon after trauma to the spinal cord. The integrity of myelin sheaths may in this way be jeopardized by apoptosis of oligodendrocytes.
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  • 6
    ISSN: 1432-1211
    Keywords: Key words Vβ13 ; CD4/CD8 ratio ; Rat ; Tcrb ; Polymorphism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract. Three rat BV13S1 alleles (T-cell receptor β-chain variable gene 13) were characterized by new BV13S1-allele specific monoclonal antibodies (18B1 and 17D5) and sequence analysis of expressed and genomic BV13S1. Two alleles were functional and designated BV13S1A1 present in strains LEW, BUF, PVG, and BV13S1A2 present in BN and WF. Their products differed by six amino acids, two of them in complementarity-determing region (CDR)1 and one in CDR2. A third nonfunctional allele, BV13S1A3P, was found in strains F344 and DA. Apart from a single nucleotide insertion, it was identical to BV13S1A2. All 12 rat strains tested showed association of TCRBC1 with BV8S2/4 alleles but not with the BV13S1 alleles, which may reflect a different gene order of the rat BV compared to mouse. BV13S1A1-encoded T-cell receptors (TCRs) which bind both monoclonal antibody (mAb) 18B1 and mAb 17D5 are over-represented in the CD4 lymphocyte subset. BV13S1A2-encoded TCRs which are stained by mAb 18B1 but not by mAb 17D5 show a slight CD8-biased expression. Preferential usage of BV13S1A1-positive TCRs by CD4 but not by CD8 cells in (LEW×WF)F1 hybrids and cosegregation of BV13SA1 and increased frequency of BV13S1 TCR-positive CD4 cells in a (LEW×BN)×BN backcross suggest structural differences of the two allelic products as the reason for their contrasting CD4/CD8 subset bias.
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  • 7
    ISSN: 1432-0738
    Keywords: Key wordsα2u-Globulin ; Diethylstilbestrol ; Endocrine disrupter ; Rat ; Screening
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract α2u-Globulin (AUG) is a major rat urinary protein, which has a molecular weight of 16 kDa (kidney type) or 19 kDa (native type). The biosynthesis of this protein is under multi-hormonal regulation. In this study, we investigated changes in serum AUG level and their association with changes in the reproductive organs of male rats after the administration of the estrogenic chemical, diethylstilbestrol (DES) at doses ranging from 0.01 mg/kg per day to 100 mg/kg per day by gavage for 14 days. Our aim was to establish basic data for the development of a new screening method for endocrine disrupting chemicals based on serum AUG levels. DES treatment decreased the weight of testes in a dose-dependent manner; and was accompanied by atrophic histopathological changes in testes. Testis weights were significantly decreased by the group given 1 mg/kg per day DES; however, histopathological abnormalities were found in the group given 0.1 mg/kg per day DES. In four of five animals in the group given 1 mg/kg per day there was no significant decrease in testis weight and only a slight or moderate degeneration of the pachytene spermatocytes. Despite these findings, serum AUG levels in this group decreased markedly, while the serum AUG level markedly decreased even in the animals with no histopathological change in the 1 mg/kg per day or 0.1 mg/kg per day groups with no histopathological change also showed decreased serum AUG level. These results suggest that the serum AUG level may be a sensitive parameter for detecting the activity of estrogenic chemicals in intact male rats. Although a uterotropic assay has been proposed for immature female or ovariectomized female rats and is currently undergoing validation studies internationally, there is no screening method for estrogenic chemicals in intact male animals. More data on AUG changes by treatment with other estrogenic chemicals are needed in order to determine the sensitivity and specificity of this response to estrogens. Nonetheless, an AUG-based screening test for estrogenic chemicals may be useful owing to its applicability to conventional toxicity studies and an apparently higher sensitivity of this parameter compared to organ weight change or histology of testis in intact male rats and applicability to conventional toxicity studies.
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  • 8
    ISSN: 1432-0738
    Keywords: Key words Flutamide ; Androgen antagonist ; Rat ; Enhanced OECD Test Guideline 407 ; Endocrine disrupters
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In association with the international validation project to establish a test protocol for the `Enhanced OECD Test Guideline 407', we performed a preliminary 28-day, repeated-dose toxicity study of flutamide, a non-steroidal androgen antagonist, and assessed the sensitivity of a list of parameters for detecting endocrine-related effects of endocrine-disrupting chemicals (EDCs). Seven-week-old CD(SD)IGS rats were divided into four groups, each consisting of 10 males and 10 females, and administered flutamide once daily by oral gavage at doses of 0 (control), 0.25, 1 and 4 mg/kg body weight/day. Male rats were killed 1 day after the 28th administration. Female rats were killed on the day they entered the diestrus stage in the estrous cycle following the last treatment. Male rats receiving flutamide at dose levels of 1 and 4 mg/kg showed lobular atrophy of the mammary gland and a decrease in epididymal weight. In addition, 4 mg/kg flutamide-treated males exhibited raised serum testosterone and estradiol levels and decreased weight of the accessory sex glands. In females, a slight prolongation of the estrous cycle was also observed in the 4 mg/kg flutamide-treated group. No dose-related changes could be detected by haematology, serum biochemistry and sperm analysis. Thus, among the parameters tested in the present experimental system, the weight of endocrine-linked organs and their histopathological assessment, serum hormone levels, and estrous cycle stage allowed the detection of endocrine-related effects of flutamide.
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Experimental brain research 130 (2000), S. 100-104 
    ISSN: 1432-1106
    Keywords: Key words NF-κB ; p65 ; Hippocampal neurons ; Glia ; Astrocytes ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  NF-κB is found in many neuronal cell types in different states of activity. This study aimed to define which conditions induce constitutive NF-κB activity in cultured hippocampal neurons using activity-specific antibody staining. In co-culture with astroglia, hippocampal neurons were devoid of activated NF-κB. In these co-cultures, NF-κB could not be activated via kainate or glutamate. In contrast, separating neurons from the glial compartment resulted in a time-dependent increase of activated neuronal NF-κB. In this line, activation of NF-κB by kainate or glutamate is very effective in freshly separated cultures, but inhibited when the cultures are reassembled after stimulation. These findings suggests that a neuronal-glial interaction may regulate gene expression via NF-κB.
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  • 10
    ISSN: 1437-9813
    Keywords: Key words Fetal transplantation ; Proliferation ; Adrenal glands ; Addisonian crisis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The present study investigated the histologic maturation, proliferative capacity, and steroid production of fetal adrenal transplants (Tx) in adrenalectomized rats. A pair of fetal adrenal glands (18–20 days of gestation) was transplanted into the omentum of syngeneic Lewis rats (n=45). Four weeks later, in 5 animals the grafts were excised for morphologic evaluation. Proliferation was investigated by immunohistochemical staining for KI-67 protein and quantified by the proliferation index (PI = positive cells/100 counts). All other hosts (Tx; n = 40) underwent bilateral adrenalectomy (AE) to induce Addisonian crisis. Postoperatively, survival and concentrations of potassium, sodium, aldosterone, and corticosterone were recorded for 6 months. These data were compared to controls (C = only AE; n = 30) and a sham group (S; n = 10). At the end of the study period all surviving hosts were killed for histologic examination of grafts. At 4 weeks post-Tx the adrenal grafts demonstrated a distinct zona glomerulosa and frequent proliferation with a PI of 0.084, comparable to normal control (0.092). Following AE survival was significantly prolonged in Tx (86% vs 12% of C, P 〈 0.05). Control animals developed severe hyponatremia and hyperkalemia, whereas in Tx only transient signs of Addisonian crisis were recorded. Levels of aldosterone dropped within 7 days in the Tx and C groups, but returned to normal for Tx within 8 weeks. Corticosterone levels of Tx animals fell to 25% within week, but steadily increased to 70% by the end of the study. At 6 months, grafts revealed a mature adrenocortical structure with little proliferative activity, which was comparable to controls. In a syngeneic rat model fetal adrenal transplants thus mature and proliferate to provide sufficient steroid production for adrenalectomized hosts.
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  • 11
    ISSN: 1437-9813
    Keywords: Key words Congenital diaphragmatic hernia ; Hypoplastic lung ; Bromodeoxyuridine (BrdU) ; Antenatal glucocorticoids ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The aim of this study was to investigate the effect of antenatal glucocorticoid therapy on smooth-muscle-cell (SMC) DNA synthesis in the pulmonary arteries (PA) in a nitrofen-induced congenital diaphragmatic hernia (CDH) rat model following nitrofen administration on day 9.5 of gestation. Antenatal dexamethasone (DEX) was given intraperitoneally on days 18.5 and 19.5 of gestation. Bromodeoxyuridine (BrdU) was injected via a jugular vein into the dam 1 h before the fetuses were killed by cesarean section at term. The fetuses were divided into three groups: group I (n = 10): normal controls; group II (n = 10): nitrofen-induced CDH; group III (n = 10): nitrofen-induced CDH with antenatal DEX treatment. Immunostaining of the lungs with anti-BrdU antibody was obtained by a standard avidin-biotin complex method. The number of immunopositive cells in the PA media and adventitia were counted using an image analyzer and analyzed statistically. The number of BrdU-immunopositive cells in the media was significantly increased in group II (16.83 ± 3.01) compared to groups I (9.16 ± 2.20) and III (6.83 ± 1.70) (P 〈 0.01). There was no significant difference between groups I and III. The number of BrdU-immunopositive cells in the adventitia was not significantly different between the three groups. Antenatal DEX treatment inhibits SMC DNA synthesis in PA media in CDH lungs. This may be a possible mechanism by which antenatal DEX prevents structural PA changes in nitrofen-induced CDH in rats.
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  • 12
    Electronic Resource
    Electronic Resource
    Springer
    Pediatric surgery international 16 (2000), S. 485-487 
    ISSN: 1437-9813
    Keywords: Key words Duodenum ; Apoptosis ; Fetus ; Rat ; Duodenal atresia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Duodenum is thought to go through a solid-core stage followed by recanalization during its development. This study investigates the role of apoptosis in normal duodenal development, especially during widening of the lumen, and hence, the possible role of apoptosis in duodenal atresia (DA). Twenty-four time-mated Sprague-Dawley rats were killed from day 13 to day 20 of gestation. Duodenums of 3 fetuses were chosen randomly from each rat and processed. Apoptosis was determined by the terminal deoxytransferase-mediated biotin dUTP nick-end labeling (TUNEL) technique (ApopTag). Apoptosis count and cross-sectional areas were measured with an image analyzer (MetaMorph). The number of apoptotic cells per unit area duodenum peaked on day 15 for the mucosal/submucosal layer and on day 14 for the muscular/mesenchymal layer. The maximal number of apoptotic cells per cross-section of duodenum was between 7 and 8. The cross-sectional areas of the duodenal wall and lumen increased exponentially between day 17 and day 19 while duodenal-wall thickness remained relatively constant throughout duodenal development. The localization, timing, and intensity of apoptosis do not suggest that apoptosis is responsible for the widening of the duodenal lumen; enlargement of the lumen is related to the increase in duodenal circumference. Apoptosis thus may not be involved in the pathogenesis of DA.
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  • 13
    ISSN: 1437-7799
    Keywords: Key words VEGF ; Glomeruli ; Ribonuclease protection assay ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background. Vascular endothelial growth factor (VEGF) is a selective endothelial growth factor which potently enhances microvascular permeability. In the kidney, VEGF mRNA is known to be highly expressed in visceral epithelial cells in glomeruli. However, the physiological role of VEGF in glomerular function and its involvement in the pathogenesis of proteinuria are not clear. The present studies were designed to determine whether altered expression of VEGF mRNA was observed in the course of puromycin aminonucleoside (PAN) nephrosis in rats (a model of human minimal change nephrosis). Methods. The message level of VEGF in isolated glomeruli of PAN nephrosis rats was measured using a ribonuclease protection assay. Results. VEGF expression began to decrease 4 days after PAN injection and could not be detected in the nephrotic stage of PAN nephrosis (on days 8 and 16). In the remission of stage of PAN nephrosis (on day 28), mRNA was restored to the control level. Conclusions. According to our results, a functional defect in the VEGF expression of visceral epithelial cells was observed in PAN nephrosis. VEGF could be a functional marker of visceral epithelial cells, and the loss of normal expression of VEGF after damage to visceral epithelial cells could affect glomerular endothelial cell function in PAN nephrosis.
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  • 14
    Electronic Resource
    Electronic Resource
    Springer
    Pediatric surgery international 16 (2000), S. 285-292 
    ISSN: 1437-9813
    Keywords: Key words Major histocompatibility complex (MHC) ; Rat ; Immunohistochemistry ; Distribution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The present study systematically investigated the expression and distribution of the major histocompatibility complex (MHC) classes I and II in the rat. About 150 native tissue probes from eight adult Lewis rats were taken, representative for most organs, tissues, and the vascular system. MHC expression was analyzed by two monoclonal antibodies (mAb) generated against the non-polymorphic determinants of rat MHC class I (Ox-18) and class II (Ox-6). Immunoreactivities were compared to those of different endothelial (HIS52, TLD-3A12, Ox-43, REHA-1 antigen), histiocytic (ED1, ED2), B-cell (RLN-9D3), and T-cell (MRC Ox-52) markers. A nonspecific mAb (MR12/53) served as a negative control. Pretested concentrations on various tissues and the alkaline phosphatase-anti-alkaline phosphatase technique allowed semiquantitative evaluation of serial cryostat tissue sections. MHC class I expression was detected on most immunocompetent cells. Endothelial cells were stained heterogeneously along the vascular system and the organ-specific microcirculation. Furthermore, some organs showed staining of parenchymal cells. MHC class II was found on all immunocompetent cells positive for the B-cell marker and about 15% of cells positive for the histiocytic markers. Besides the well-known expression of MHC class II in the outer zone of the renal proximal tubule, further organ-specific cell forms were found positive. In conclusion, the present study outlines tissue-specific distribution of MHC I/II and implies that each organ carries a variable immunologic burden that needs to be considered for any transplantation model.
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  • 15
    ISSN: 1436-2023
    Keywords: Key words Adriamycin ; Rat ; Embryo ; VATER association ; Synovial joint ; Bones ; Limbs ; Vertebra ; Sirenomelia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The adriamycin-induced rat model of the Vertebral, Anorectal, Tracheo-Esophageal, Radial and Renal (VATER) association produces a variety of vertebral, rib, and limb abnormalities. This study was designed to document accurately the nature of these abnormalities and to determine whether synovial joints are affected. Fetuses from pregnant Sprague Dawley rats that had received intraperitoneal injections of 1.75 mg/kg of adriamycin on days 6–9 or 10–13 of gestation were harvested. Double-stained skeletal preparations and histological sections were examined for vertebral, rib, and limb anomalies. The incidence of anomalies was high in the group treated on gestational days (GD) 6–9, while it was low in the GD 10–13 group. The length and thickness of the long bones were reduced, with bowing and reduction in their endochondral ossification. Sirenomelia occurred in the group treated on GD 6–9, and was often associated with a short tail and anal atresia. The joint cavities, and intra-articular structures such as menisci and the cruciate ligaments developed normally from the mesenchymal interzone. These data indicate that adriamycin inhibits skeletal growth and differentiation without any interference in the differentiation of the mesenchymal interzone, thus producing normal synovial joints.
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  • 16
    ISSN: 1432-0843
    Keywords: Key words 7-Hydroxymethotrexate ; Methotrexate ; Maximum tolerated dose ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: After more than 50 years of methotrexate (MTX) treatment of acute lymphoblastic leukaemia (ALL), it is currently believed that as long as dose escalations are followed by adequate leucovorin rescue guided by monitoring MTX serum concentrations, hydration and urinary alkalinization, high-dose MTX (HD-MTX) can be tolerated without life-threatening toxicity. However, our recent experimental animal studies of the major metabolite of MTX, 7-OH-MTX, indicate that this concept may have some limitations. Animals with levels of 7-OH-MTX of 1 mM, which is below the levels routinely found in patients on HD-MTX, demonstrate intolerable toxicity and some animals die within 8 h. Electron microscopy indicates that endothelial cell and platelet functions are perturbed. Since animal data are lacking, and interspecies differences not known, we wanted to investigate the maximum tolerated doses of MTX and 7-OH-MTX in a rat model of short-term effects. The maximum tolerated dose was chosen instead of LD50 for reasons of animal welfare. Methods: We infused MTX and 7-OH-MTX into anaesthetized male Wistar rats and monitored the animals for 8 h. The drugs were given as a bolus plus continuous infusion. The dose-finding ranges were 1.8–11.3 g/kg MTX and 0.1–1.2 g/kg 7-OH-MTX. Results: The maximum tolerated dose was between 3 and 5 g/kg for MTX and lower than 0.1 g/kg for 7-OH-MTX. The mean serum concentrations of MTX and 7-OH-MTX in animals that did not survive the 8-h period were 21.9 and 1.6 mM, respectively. The animals that received the highest MTX or 7-OH-MTX doses and concentrations died after sudden reductions in heart rate and blood pressure. Conclusions: We demonstrated a lower maximum tolerated dose of 7-OH-MTX than of MTX in rats after 8 h. The 7-OH-MTX concentrations were in the therapeutic range after HD-MTX. If the rat/human interspecies differences are not large, our data may indicate that HD-MTX regimens should not be further dose intensified, due not so much to the effects of MTX as to those of 7-OH-MTX.
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  • 17
    Electronic Resource
    Electronic Resource
    Springer
    Journal of cancer research and clinical oncology 126 (2000), S. 27-32 
    ISSN: 1432-1335
    Keywords: Key words Heart irradiation ; Plasma enzyme levels ; Myocardial enzyme levels ; Rat ; AbbreviationsCK creatine kinase ; LDH lactate de-hydrogenase ; AST aspartate aminotransferase ; ALT alanine aminotransferase ; α-HBDHα-hydroxybutyrate dehydrogenase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Plasma levels of myocardial enzymes present after local heart irradiation were studied in a rat model. The purpose was to investigate whether, within days after irradiation, these enzyme levels change to such an extent that they may be helpful in assessing the severity of cardiac damage after radiotherapy. Therefore, activities of creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and α-hydroxybutyrate dehydrogenase (α-HBDH) were determined in the plasma and left ventricular myocardium of rats following local heart irradiation with a single dose of 20 Gy. A dose of 20 Gy is known to cause irreversible cardiac damage and to reduce survival times of the animals. Cardiac enzyme assays were performed directly after and twice daily for up to 2 weeks after radiation. Plasma CK, LDH, AST and α-HBDH levels were increased between 2 h and 24 h after irradiation. Plasma ALT levels remained unchanged. Myocardial enzyme levels, measured between 24 h and 16 days after radiation, did not differ between irradiated and control animals, although acute (first 12 h) reductions were observed in the irradiated group. The elevated enzyme levels in plasma appeared to correlate with the acutely reduced myocardial enzyme levels. Although irradiation with a dose of 20 Gy induced acute rises of cardiac enzyme levels in plasma, it is doubtful that fractionated radiation, as applied clinically for treatment of solid tumors, will induce plasma enzyme elevations that are large enough to indicate the extent of cardiac damage occurring acutely or chronically.
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  • 18
    ISSN: 1432-198X
    Keywords: Key words Apoptosis ; Ceramide ; Development ; Kidney ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Ceramide is emerging as an important hydrophobic sphingolipid involved in cell differentiation and apoptosis. Since apoptosis plays a significant role in cellular remodeling during renal morphogenesis, we measured ceramide content and apoptosis in the fetal (18 days gestation), neonatal (3, 7, and 14 days postnatal), and adult rat kidney. In addition, to determine whether developmental changes in ceramide content are tissue-specific, we compared renal ceramide content with that in lung and liver. Ceramide was measured by the diacylglycerol kinase assay, and apoptosis was determined by the TUNEL technique. Renal ceramide content fell over 100-fold from the fetus to the 7th postnatal day. Renal apoptosis paralleled ceramide content, with a greater than 300-fold decrease in apoptosis from fetal to adult life. Ceramide content of the lung and liver was significantly less than that of the kidney, and changed less with maturation. We conclude that maturational changes in ceramide content are tissue-specific, and that the high rate of apoptosis in the developing kidney may be related to the elevated ceramide content.
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  • 19
    ISSN: 1432-198X
    Keywords: Key words Metabolic acidosis ; Growth ; Growth hormone ; Insulin-like growth factor-I ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Growth impairment induced by chronic metabolic acidosis is associated with an abnormal growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. To examine the potentially beneficial effects of IGF-I on acidosis-induced growth impairment and the influence of GH and IGF-I treatment on the GH/IGF-I axis, three groups of acidotic young rats (untreated, AC, n=12; treated with recombinant human GH, GH, n=8; treated with recombinant human IGF-I, IGF-I, n=8) were studied, and compared with nonacidotic rats fed ad libitum (C, n=9)) or pair-fed with the AC group (PF, n=12). After 14 days of acidosis and 7 days of treatment, growth rate, hepatic abundance of 4.7-kilobase (kb) and 1.2-kb GH receptor transcripts and 7.5-kb and 1.8- to 0.8-kb IGF-I transcripts, serum GH-binding protein (GHBP), and IGF-I concentrations (mean±SEM) were analyzed. Significant decreases of 4.7-kb GH receptor [26±2 vs. 49±6 arbitrary densitometry units (ADU)] and 7.5 kb IGF-I (41±3 vs. 104±10 ADU) transcripts and low serum GHBP (25±1 vs. 32±1 ng/ml) and IGF-I (279±50 vs. 366±6 nmol/l) levels were found in the AC compared with the C rats. The majority of these alterations were also observed in PF rats. Compared with acidotic untreated rats, GH and IGF-I therapy produced no improvement in growth rate. GH treatment normalized the levels of IGF-I mRNA, aggravated the acidosis-related inhibition of the GH receptor gene, and did not modify the serum levels of GHBP and IGF-I. In contrast, IGF-I administration depressed the hepatic expression of all GH and IGF-I transcripts and normalized serum IGF-I concentrations. Our results confirm that sustained metabolic acidosis alters the GH/IGF-I axis, in part because of associated malnutrition, and induced growth retardation that is resistant to GH therapy. Our study also shows that administration of IGF-I does not accelerate the growth of acidotic rats, suggesting a peripheral mechanism, at the level of target tissues, is responsible for the resistance to the growth-promoting actions of GH and IGF-I.
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  • 20
    ISSN: 1432-119X
    Keywords: Endothelin-A receptor ; Endothelin-B receptor ; Rat ; Pulmonary fibrosis ; Immunohistochemistry ; Quantitative PCR
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: AbstractPulmonary fibrosis is characterized by excessive extracellular matrix deposition with concomitant loss of gas exchange units, and endothelin-1 (ET-1) has been implicated in its pathogenesis. Increased levels of ET-1 from tissues and bronchoalveolar lavage have been reported in patients with pulmonary fibrosis and in animal models after intratracheal bleomycin. We characterized the cellular distribution of alveolar ET receptors by immunohistochemistry in bleomycin-induced pulmonary fibrosis in the rat and determined the regulation by bleomycin of ET receptor mRNA expression in isolated alveolar macrophages and rat lung fibroblasts. We found significant increases in the numbers of fibroblasts and macrophages at day 7 compared to day 28 and control animals. ETB receptor immunoreactivity was observed on fibroblasts and invading monocytes. Isolated fibroblasts expressed both ETA and ETB receptor mRNA, and ETA receptor mRNA was upregulated by bleomycin. Isolated resident alveolar macrophages expressed neither ETA nor ETB receptor mRNA which were also not induced by bleomycin. We conclude that, while ETB receptor stimulation of fibroblasts and monocytes recruited during bleomycin-induced lung injury exerts antagonistic effects on fibroblast collagen synthesis, the observed increase in the number of fibroblasts in vivo and upregulation of fibroblast ETA receptor mRNA by bleomycin in vitro point to a predominance of the profibrotic effects of ET receptor engagement.
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  • 21
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    Psychopharmacology 148 (2000), S. 146-152 
    ISSN: 1432-2072
    Keywords: Key words Alprazolam ; Drug discrimination ; Benzodiazepines ; Antidepressant ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The triazolobenzodiazepine alprazolam has a unique clinical profile compared to most other benzodiazepines (e.g. diazepam, chlordiazepoxide), in that it is used to treat panic disorder and is effective in depression, two disorders that are usually treated with anti-depressants. Previous drug discrimination studies suggested that alprazolam has stimulus properties in common with antidepressants. Objective: In the present study, the discriminative stimulus properties of alprazolam were investigated to test more conclusively the role of benzodiazepine receptors and whether alprazolam has stimulus properties in common with antidepressants. Methods: Male Wistar rats (n=12) were trained to discriminate between alprazolam (2.0 mg/kg, PO) and vehicle in an operant two-lever drug discrimination procedure under a tandem VI40”-FR10 schedule of reinforcement. Generalization and antagonism tests were carried out under 2 min extinction. Results: In generalization tests, a number of benzodiazepines (alprazolam, chlordiazepoxide, midazolam, lorazepam) and the barbiturate pentobarbital substituted completely, while zolpidem and abecarnil substituted partially for alprazolam. In contrast, no significant degree of generalization to the antidepressants imipramine and fluvoxamine and the putative antidepressants buspirone and flesinoxan was found. In antagonism studies alprazolam could be antagonized (almost) completely by flumazenil, partially by pentylenetetrazole, but not by methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), N-methyl-β-carboline-3-carboxamide (FG-7142) and picrotoxin. Conclusions: These results show that the discriminative stimulus properties of alprazolam are mediated by benzodiazepine receptors and that the finding that antidepressants share discriminative stimulus effects with alprazolam may have limited generality.
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  • 22
    ISSN: 1432-2072
    Keywords: Key words 5-HT1A agonist ; Intrinsic activity ; Efficacy ; Irreversible antagonism ; Lower-lip retraction ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Maximal responses are often used as a measure of intrinsic activity or efficacy, but cannot be directly equated to efficacy. Using irreversible antagonists, estimates of efficacy can be obtained that may be less dependent on specific conditions. Objectives: To characterize the intrinsic activity of serotonin (5-HT)1A agonists by examining the effects of an irreversible antagonist on their ability to produce 5-HT1A receptor-mediated responses. Methods: The effects of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) on the ability of 5-HT1A agonists to produce lower-lip retraction (LLR) in rats were studied. Results: In the absence of EEDQ, each 5-HT1A agonist produced full effects, the rank order of potency being: S 14506 〉 8-OH-DPAT 〉 buspirone 〉 ipsapirone. EEDQ decreased the number of 5-HT1A binding sites and shifted the dose–response curves (DRCs) of each agonist either to the right or, at higher EEDQ doses, to the right and downward. The manner in which these shifts occurred, however, differed among the compounds. For each agonist, all DRCs obtained after different doses of EEDQ were fitted to models proposed by Furchgott and Black and Leff, and the results indicated the following rank order of efficacy: ipsapirone 〈 buspirone ≈ 8-OH-DPAT 〈 S 14506. 5-HT1A agonist-induced LLR appears to be mediated by 5-HT1A receptors, because the 5-HT1A antagonist, WAY 100635, shifted the agonist DRCs to the right in a parallel and dose-related manner, with pA2 values ranging from 7.8 to 8.1. Moreover, pretreatment with WAY 100635 protected against the antagonist activity of EEDQ. Conclusions: The results suggest that the effects of EEDQ on the ability of 5-HT1A agonists to produce LLR in rats may be useful to obtain estimates of their apparent efficacy at 5-HT1A receptors.
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  • 23
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    Psychopharmacology 148 (2000), S. 209-216 
    ISSN: 1432-2072
    Keywords: Key words Methamphetamine ; Drug-discrimination ; Dopamine ; Cocaine ; GBR-12909 ; Nomifensine ; Bupropion ; Chloro-PB ; Chloro-APB ; NPA ; 7-OH-DPAT ; SCH-23390 ; Spiperone ; cis-Flupenthixol ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Dopamine plays a major role in the behavioral effects of methamphetamine. Objective: In the present experiments, the effects of different dopaminergic agonists, antagonists, and uptake inhibitors were evaluated in rats discriminating methamphetamine from saline. Methods: In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine, i.p., from saline under a fixed-ratio schedule of food delivery, the ability of various dopaminergic agonists and uptake inhibitors to substitute for methamphetamine was evaluated. Subsequently, the ability of various dopaminergic antagonists to block the discriminative-stimulus effects of the training dose of methamphetamine was tested. Results: The dopamine-uptake inhibitors cocaine (10.0 mg/kg), nomifensine (3.0 mg/kg), GBR-12909 (18.0 mg/kg), and bupropion (30.0 mg/kg) fully substituted for the 1.0 mg/kg training dose of methamphetamine. Chloro-APB (SKF-82958), a full agonist at D1 dopamine receptors, produced about 85% methamphetamine-appropriate responding, but the dose required (0.18 mg/kg) markedly decreased rates of responding. Chloro-PB (SKF-81297), another agonist at D1 receptors with a lower intrinsic activity than Chloro-APB, produced only partial generalization (maximum about 55%) at a dose of 1.0 mg/kg. Full substitution for the training dose of methamphetamine was observed with 0.03 mg/kg of the D2 agonist NPA and 0.56 mg/kg of the D3/D2 agonist 7-OH-DPAT. Both NPA and 7-OH-DPAT markedly decreased rates of responding at these doses. The D1 antagonist SCH-23390 (0.056 mg/kg), the D2 antagonist spiperone (0.18 mg/kg), and the mixed D1,D2 antagonist cis-flupenthixol (0.56 mg/kg) all completely blocked the discriminative-stimulus actions of the training dose of methamphetamine. Conclusions: The present findings in rats support previous research findings in other species indicating a major role of dopamine in the discriminative-stimulus effects of methamphetamine. These findings further indicate involvement of dopamine uptake sites as well as D1 and D2 receptors.
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  • 24
    ISSN: 1432-2072
    Keywords: Key words Drug discrimination ; Olanzapine ; Clozapine ; Chlorpromazine ; Haloperidol ; Thioridazine ; Raclopride ; Risperidone ; Scopolamine ; Ritanserin ; Atypical antipsychotic ; Neuroleptic ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Analysis of the preclinical behavioral effects of atypical antipsychotic agents will provide a better understanding of how they differ from typical antipsychotics and aid in the development of future atypical antipsychotic drugs. Objectives: The present study was designed to provide information about the discriminative stimulus properties of the atypical antipsychotic olanzapine. Methods: Rats were trained to discriminate the atypical antipsychotic olanzapine (either 0.5 mg/kg OLZ or 0.25 mg/kg OLZ, i.p.) from vehicle in a two- lever drug discrimination procedure. The atypical antipsychotic clozapine fully substituted for olanzapine in both the 0.5-mg/kg OLZ group (99.3% drug lever responding [DLR]) and the 0.25-mg/kg OLZ group (99.9% DLR). The typical antipsychotic chlorpromazine also substituted for olanzapine in both the 0.5-mg/kg OLZ group (87.5% DLR) and in the 0.25-mg/kg OLZ group (98.9% DLR); whereas, haloperidol displayed partial substitution for olanzapine in the 0.5-mg/kg OLZ group (56.1% DLR) and in the 0.25-mg/kg OLZ group (76.4% DLR). The 5.0-mg/kg dose of thioridazine produced olanzapine-appropriate responding in the 0.5-mg/kg OLZ group (99.6% DLR), but only partial substitution was seen with the 0.25-mg/kg OLZ training dose (64.0% DLR). The atypical antipsychotics raclopride (53.9% DLR) and risperidone (60.1% DLR) displayed only partial substitution in the 0.5-mg/kg OLZ group. Both the muscarinic cholinergic antagonist scopolamine (90.0% DLR) and the 5-HT2A/2C serotonergic antagonist ritanserin (86.0% DLR) fully substituted for olanzapine in the 0.5-mg/kg OLZ group. Conclusions: In contrast to previous discrimination studies with clozapine-trained rats, the typical antipsychotic agents chlorpromazine and thioridazine and the serotonin antagonist ritanserin substituted for olanzapine. These results demonstrate that there are differences in the mechanisms underlying the discriminative stimulus properties of clozapine and olanzapine. Specifically, olanzapine’s discriminative stimulus properties appear to be meditated in part by both cholinergic and serotonergic mechanisms.
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  • 25
    ISSN: 1432-2072
    Keywords: Key words Nicotine ; Drug discrimination ; Self-administration ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The cellular effects of nicotine underlying its addictive liability are thought to be mediated by neuronal nicotinic receptors (nACHRs) in the central nervous system. It is believed that densely expressed β2-containing nACHRs in the central nervous system are responsible for these actions, but few data are available that can directly assess subtype mediation of nicotine’s acute subjective and reinforcing effects. Objective: The present study compared the effects of the competitive nACHR antagonist erysodine and the noncompetitive antagonist mecamylamine in rats trained to discriminate or self-administer nicotine. Methods: Adult male rats were trained to disciminate 0.4-mg/kg injections of nicotine from vehicle in a two-lever procedure of food-maintained behavior, or to self-administer 0.03-mg/kg injections of nicotine under fixed-ratio 5 or progressive-ratio schedules of reinforcement. Additional rats were trained under a food-maintained procedure of lever pressing. Results: Erysodine (0.3–10 mg/kg) and mecamylamine (0.1–1.0 mg/kg) blocked nicotine discrimination, although only erysodine produced the rightward shift that would be predicted of a competitive antagonist. Erysodine (0.32–32 mg/kg) and mecamylamine (0.32–3.2 mg/kg) also selectively reduced nicotine self-administration on a fixed-ratio schedule and lowered break points on a progressive-ratio schedule. Conclusions: Based on the known affinity of erysodine for α4β2 nACHRs and its selectivity relative to α7 and α1β1γδ receptors, the present data support a critical role of β2-containing nACHR constructs in the discriminative and reinforcing actions of nicotine.
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  • 26
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    Psychopharmacology 148 (2000), S. 243-250 
    ISSN: 1432-2072
    Keywords: Key words Attention ; Scopolamine ; Mecamylamine ; Oxotremorine ; Physostigmine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: This study tried to determine the relative roles of muscarinic and nicotinic cholinergic receptors in attentional processing. Methods: The effects of cholinoceptor agonists and antagonists, and of an anticholinesterase, were studied on performance of rats in a five-choice serial reaction time task. Results: Scopolamine (0.1 mg/kg) and mecamylamine (5.0 mg/kg) produced deficits in accuracy and reaction time, respectively. This may suggest a differential role for the two types of cholinoceptors in information processing. Combinations of sub-threshold doses of scopolamine (0.01–0.03 mg/kg) and mecamylamine (0.5–1.6 mg/kg), which alone did not affect accuracy or reaction time, did not produce significant deficits in attention. However, the pattern of effects after combined treatment suggested that the differential deficits seen with these drugs alone remained. The anticholinesterase physostigmine (0.1 mg/kg) and the non- selective muscarinic agonist oxotremorine (0.03 mg/kg) induced severe behavioural disruption at doses that appeared to be relatively well tolerated in previous studies; this precluded the derivation of accuracy and response time data at these doses. At lower doses, neither physostigmine (0.05 mg/kg) nor oxotremorine (0.003 mg/kg) significantly affected any performance measure; this may reflect the ability of both drugs to indirectly or directly activate presynaptic muscarinic receptors that inhibit acetylcholine release, respectively. Conclusions: Both muscarinic and nicotinic cholinoceptors may be important in attention but they may serve different roles in information processing; this hypothesis could be tested using tasks that place different emphasis on different stages of information processing.
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  • 27
    ISSN: 1432-2072
    Keywords: Key words Morphine ; Opioid receptor ; NMDA ; Tolerance ; Rat ; Tail flick
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Pairings of a sweet taste and injection of morphine result in a learned avoidance of that taste and learned analgesic tolerance. This avoidance is mediated by the drug’s peripheral effect, while learned tolerance involves activation of N-methyl-d-aspartate (NMDA) receptors. Exposure to a sweet taste also reduces morphine analgesia. We studied whether this taste-mediated reduction was reversed by an NMDA or peripheral opioid receptor antagonist. Objectives: To determine whether an intraoral infusion of saccharin would modulate morphine analgesia in rats, and to study the contribution of NMDA as well as peripheral opioid receptors to this modulation. Methods: Six experiments used the rat’s tail-flick response to study the effect of an intraoral infusion of a sodium saccharin solution on morphine analgesia, and the effects of the quaternary opioid receptor antagonist methylnaltrexone as well as the non-competitive NMDA receptor antagonist MK-801 on this modulation of analgesia. Results: An intraoral infusion of saccharin reduced the analgesic effects of an intraperitoneal (i.p.) injection of morphine across a range of doses (experiment 1a), which was not attributable to an influence on tail-skin temperature (experiment 1b). This reduction was mediated by opioid receptors in the periphery and activation of NMDA receptors because morphine analgesia was reinstated by an i.p. injection of either methylnaltrexone (experiment 2a) or MK-801 (experiment 3a), which was not due to the effect of methylnaltrexone (experiment 2b) or MK-801 (experiment 3b) on morphine analgesia in the absence of saccharin. Conclusions: These results document evidence for an antagonism of morphine analgesia by actions of the drug at peripheral opioid receptors and excitatory amino-acid activity at NMDA receptors. They are discussed with reference to the aversive motivational effects of peripheral opioid receptors and pain facilitatory circuits.
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  • 28
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    Psychopharmacology 149 (2000), S. 115-120 
    ISSN: 1432-2072
    Keywords: Key words Opiate ; Withdrawal ; Place aversion ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Administration of low doses of opiate antagonists to morphine-dependent rats produces an aversive response as measured by a conditioned place aversion, but the time course of such a learned aversion is largely unknown. Objectives: The purpose of this experiment was to examine the time course for the expression of a place aversion to opiate withdrawal. Methods: Morphine-dependent rats were tested in a three-chamber place- aversion apparatus. The conditioning phase consisted of three pairings of either naloxone (15 µg/kg s.c.) or vehicle with two compartments, with the most similar time allotments during the preconditioning test. During the testing phase, rats were again allowed to explore the entire apparatus. Different groups were tested at 24 h, 1 week, 2 weeks, 4 weeks, 8 weeks, and 16 weeks post-conditioning (morphine-free tests). Results: A robust place aversion was recorded at every time point tested, including at 16 weeks. In previously published work, placebo-pelleted rats tested with naloxone at the same dose failed to show a place aversion and nondependent rats showed a stable lack of aversion at tests up to 56 days. Dependent animals without naloxone also failed to show a place aversion at any of those time points. Conclusions: In the absence of any active intervention, the place aversion produced by opiate withdrawal is very long lasting and provides a model for protracted abstinence that may be useful for delineating the neurobiological substrate for vulnerability to relapse.
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  • 29
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    Psychopharmacology 149 (2000), S. 181-188 
    ISSN: 1432-2072
    Keywords: Key words Acoustic startle response ; Prepulse inhibition ; Sensorimotor gating ; Schizophrenia ; Dopamine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Prepulse inhibition of acoustic startle is the reduction in startle response to an intense auditory stimulus when this stimulus is immediately preceded by a weaker prestimulus. Prepulse inhibition occurs normally in humans and experimental animals, but schizophrenic persons often exhibit a marked impairment in this measure. Previous studies have shown that dopamine (DA)-dependent neuronal mechanisms are involved in the modulation of prepulse inhibition. Objective: Experiments were conducted in rats to elucidate further the involvement of DA-ergic mechanisms in prepulse inhibition. Results: In line with previous studies, the indirect DA agonist, amphetamine, was shown to decrease prepulse inhibition. A close reverse relationship over time between DA overflow in the nucleus accumbens and prepulse inhibition was obtained using a technique allowing concomitant measurement of these parameters in awake, freely moving rats. This effect was more pronounced in amphetamine-treated rats compared to rats treated with equimolar doses of cocaine, which increased DA overflow without affecting prepulse inhibition. In other experiments, the combined treatment with subthreshold doses of the selective DA D1 agonist, SKF 38393, and the selective DA D2 agonist, quinpirole, was also shown to decrease prepulse inhibition. Finally, the selective DA D2 antagonist, raclopride, was shown to enhance prepulse inhibition. Conclusions: In line with previous studies, it is concluded that DA neurotransmission is involved in the modulation of prepulse inhibition and that the ventral part of the mesostriatal DA system may serve an important role in this modulation. Furthermore, the possibility is discussed that the discrepant results on prepulse inhibition obtained with amphetamine and cocaine may disclose functionally relevant differences in their mechanisms of action, and that the enhancement of prepulse inhibition induced by some antipsychotics in rats may reflect their propensity to induce adverse mental effects in humans.
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  • 30
    ISSN: 1432-2072
    Keywords: Key words Prefrontal cortex ; Dopamine ; Anxiety ; Drug discrimination ; Pentylenetetrazol ; Chlordiazepoxide ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The prefrontal cortical (PFC) dopamine (DA) system has been implicated in anxiety-related behavioral changes, but direct, unequivocal support for this idea is sparse. Objectives: The present aim was to study the functional significance of prefrontal DA using the pentylenetetrazol (PTZ) discrimination model of anxiety. A comparison was made with its role in the cue of the anxiolytic drug chlordiazepoxide (CDP). Methods: Two groups of rats were trained to discriminate either PTZ (20 mg/kg, s.c.) or CDP (10 mg/kg, i.p.) from saline using an operant drug discrimination procedure. After prolonged training, half of each group was used to assess biochemical changes induced by both drugs in different sub areas of the PFC. For the remaining rats, discrimination training continued and generalization tests with PTZ and CDP were performed. Rats were then provided with bilateral guide cannulae aimed at the ventromedial (vm) PFC, and the effects of local infusions of DAergic drugs on discriminative performance were evaluated. Results: CDP did not affect PFC DA activity, but PTZ increased the DOPAC/DA ratio in the vmPFC selectively. Generalization tests showed that the cues of PTZ and CDP were dose dependent. In PTZ-trained rats, infusions of the DA receptor antagonist cis-flupenthixol into the vmPFC blocked the PTZ cue dose dependently, whereas the agonist apomorphine partially generalized to this cue. In CDP-trained rats, neither drug antagonized or generalized to the CDP cue, showing that PFC DA is not critically involved in the CDP cue and that local pharmacological manipulations of PFC DA do not affect discriminative abilities per se. Conclusions: The DAergic innervation of the PFC is directly involved in the behavioral effects of PTZ, suggesting a role for it in anxiety.
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  • 31
    ISSN: 1432-2072
    Keywords: Keywords Novelty ; Context ; Environment ; Stress ; 6-OHDA ; Rotational behavior ; Striatum ; Nucleus accumbens shell ; Caudate ; Amphetamine ; Dopamine ; Glutamate ; Aspartate ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: We have previously shown that environmental novelty enhances the behavioral activating effects of amphetamine and amphetamine-induced expression of the immediate early gene c-fos in the striatal complex, particularly in the most caudal portion of the caudate. In contrast, we found no effect of novelty on the ability of amphetamine to induce dopamine (DA) overflow in the rostral caudate or in the core of the nucleus accumbens. Objectives: The twofold aim of the present study was to determine the effect of environmental novelty on (1) amphetamine-induced DA overflow in the shell of the nucleus accumbens and in the caudal portions of the caudate, and (2) glutamate and aspartate overflow in the caudal portions of the caudate. Methods: Two groups of rats with a unilateral 6-hydroxydopamine lesion of the mesostriatal dopaminergic system received amphetamine (0.5 mg/kg, i.v.) in physically identical cages. For one group, the cages were also the home environment, whereas, for the other group, they were a completely novel environment. In vivo microdialysis was used to estimate DA, glutamate, and aspartate concentrations. Results: Environmental novelty enhanced amphetamine-induced rotational behavior (experiments 1–3) but did not alter amphetamine-induced DA overflow in either the shell of the nucleus accumbens (experiment 1) or the caudate (experiment 2). In addition, the ability of environmental novelty to enhance amphetamine-induced behavioral activation was not associated with changes in glutamate or aspartate efflux in the caudate (experiment 3). Conclusions: The present data indicate that the psychomotor activating effects of amphetamine can be modulated by environmental context independent of its primary neuropharmacological actions in the striatal complex.
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  • 32
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    Psychopharmacology 151 (2000), S. 219-225 
    ISSN: 1432-2072
    Keywords: Keywords Amphetamine ; Wheel running ; Behavioral sensitization ; Pharmacological sensitization ; Novelty ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: This study explored whether repeated injections of amphetamine (AMP), which increase general locomotion, also increase acute wheel running, a highly structured, rewarding, motor behavior not correlated with other locomotor activities. Objectives: The experiments determine how 1–5 mg/kg d-AMP affects wheel running and see if, over repeated injections, the AMP effects show context specific sensitization. Methods: In experiment 1, 2 mg/kg AMP or saline (SAL) was injected on days 1, 3, 6, 8, and 10 to male Sprague-Dawley rats with either limited or no wheel experience. 20 min after the injection animals were tested in an open field for 5 min and then in a running wheel for 1 h. Rats were injected with SAL or AMP on the days following testing. On days 13 and 15, animals were tested for conditioning (following SAL) and sensitization (following AMP). In experiment 2, the effects on wheel running of repeated 1, 2, or 5 mg/kg AMP were tested. Results: In experiment 1, AMP (2 mg/kg) elevated open field ambulation but suppressed wheel running. Limited wheel experience potentiated the AMP-induced suppression. At test, the suppression of running was found to be context specific. In experiment 2, 1 mg/kg did not affect running, while 2 and 5 mg/kg resulted in dose-dependent running suppression. Acquisition and test AMP dose both influenced the running suppression at test; context had a marginal influence. Conclusions: The degree of running suppression induced by repeated AMP is determined by both psychological (the injection context) and pharmacological (the acquisition dose) factors. This AMP-induced running suppression is consistent with the sensitization of stereotyped behavior.
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  • 33
    ISSN: 1432-2072
    Keywords: Key words Fentanyl ; mu opioids ; Drug discrimination ; Training dose ; pA2 analysis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Discriminative stimulus effects of mu opioids vary systematically as a function of training dose. Differences among training doses may arise from multiple mechanisms. Objectives: In vivo apparent pA2 analyses were used to examine the contributions of opioid mechanisms to stimulus control by low and high training doses of the mu opioid fentanyl. Methods: Saline and one of two doses of fentanyl, administered s.c., were established as discriminative stimuli in two groups of rats (low training dose group: 0.01 mg/kg; high training dose group: 0.04 mg/kg). Generalization tests and in vivo apparent pA2 analyses were used to evaluate receptor mechanisms of stimulus control. Results: Fentanyl, etonitazene, methadone, and morphine evoked full fentanyl generalization in both groups but were more potent in the low-dose group. Spiradoline and d-amphetamine did not evoke generalization in either group. Naltrexone antagonized stimulus and rate-altering effects of fentanyl in both groups, with apparent pA2 values of 7.6 in the low-dose group and 7.5 in the high-dose group. Nalbuphine and nalorphine evoked full generalization in the low-dose group but less than 40% generalization in the high-dose group. In the high-dose group, nalbuphine and nalorphine antagonized the stimulus and rate-altering effects of fentanyl with apparent pA2 values of 5.3 and 6.1, respectively, demonstrating lower efficacy mu actions. Conclusions: Changes in fentanyl training dose preserved the mu opioid selectivity of stimulus control but altered the intensity of the transduced mu opioid stimulus required for generalization. These differences in intensity of the fentanyl stimulus determined whether low efficacy mu opioids would evoke or antagonize fentanyl generalization.
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  • 34
    ISSN: 1432-2072
    Keywords: Key words ACTH ; Corticosterone ; GABA ; Noradrenaline ; Adrenaline ; Stress ; Rat ; Diazepam
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Gabolysat PC60 is a fish protein hydrolysate with anxiolytic properties commonly used as a nutritional supplement. Objective: The diazepam-like effects of PC60 on stress responsiveness of the rat pituitary-adrenal system and on sympathoadrenal activity were studied. Methods: The activity of the pituitary-adrenal axis, measured by plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone (B) of the sympathoadrenal complex, measured by circulating levels of noradrenaline (NA) and adrenaline (A), and the gamma aminobutyric acid (GABA) content in the hippocampus and the hypothalamus were investigated in male rats which received daily, by an intragastric feeding tube, for 5 days running either diazepam (1 mg/kg) or PC60 (300 or 1200 mg/kg). Controls received only solvent (carboxymethylcellulose 1%). Six hours after the last force-feeding, the rats were subjected to 3 min ether inhalation or 30 min restraint and killed by decapitation 30 min after ether stress or at the end of restraint. Results: Baseline plasma levels of ACTH, B, NA and A were not affected by either diazepam or PC60. Both ether- and restraint-induced release of ACTH, but not B, were similarly and drastically reduced by diazepam and PC60 (1200 mg/kg). Both diazepam and PC60 (1200 mg/kg) deleted restraint-induced NA and A increases. Both treatments also reduced the ether-induced rise of A. Basal levels of GABA were significantly increased in both the hippocampus and the hypothalamus in PC60-treated rats and only in the hippocampus in diazepam-treated ones. In controls, ether inhalation as well as restraint increased GABA content of these two brain structures. In contrast, such stress procedures performed in PC60-treated rats reduced GABA content slightly in the hippocampus but significantly in the hypothalamus. In diazepam-treated rats, GABA content of the hypothalamus was unaffected by stresses but that of the hippocampus was slightly decreased. Conclusions: Present data suggest diazepam-like effects of PC60 on stress responsiveness of the rat pituitary adrenal axis and the sympathoadrenal activity as well as GABA content of the hippocampus and the hypothalamus under resting and stress conditions. These effects of PC60 agree with anxiolytic properties of this nutritional supplement, previously reported in both rats and humans.
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  • 35
    ISSN: 1432-2072
    Keywords: Key words  m-Chlorophenylpiperazine ; Drug discrimination ; Ethanol withdrawal ; Anxiety ; 17β-estradiol ; Sex difference ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The serotonergic system plays a role in regulation of anxiety and ethanol withdrawal (EW). Nevertheless, few studies have assessed sex differences in serotonergic effects on EW. Objectives: This study examined sex differences in the anxiogenic stimu-li induced by a serotonin (5-HT)1b/2 agonist, meta- chlorophenylpiperazine (mCPP), prior to ethanol and during EW. Methods: Gonadectomized or sham-operated adult male and female rats and 17β-estradiol (2.5 mg, 21-day release, s.c.) -replaced ovariectomized (OVX) rats were trained to discriminate mCPP (1.2 mg/kg, i.p.) from saline in a two-lever choice task for food. Latency to the first lever press and mCPP lever selection were measured following mCPP (0–1.2 mg/kg). Rats then received chronic ethanol-containing liquid diet (6.5%) for 10 days and were tested for mCPP lever selection 12 h and 36 h after removal of ethanol. Results: Fewer sham female and β-estradiol-replaced OVX rats selected the mCPP lever than male or OVX rats, and showed an increased initiation latency after mCPP injection. During EW (12 h and 36 h), fewer sham female and β-estradiol-replaced OVX rats responded on the mCPP-lever after saline injection as well as after mCPP challenge than male or OVX rats. Castration did not alter any response of male rats to mCPP. Conclusions: (1) mCPP discrimination is a useful measure of EW in male and female rats; and (2) sham female and β-estradiol-replaced OVX rats are less sensitive to the discriminative stimulus prior to and during EW, but more sensitive to impaired behavioral initiation induced by mCPP than male or OVX rats.
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  • 36
    ISSN: 1432-2072
    Keywords: Key words 8-OH-DPAT ; WAY 100635 ; 5 ; 7-Dihydroxytryptamine ; Attention ; Impulsivity ; Pre- and postsynaptic 5-HT1A receptor ; Dorsal raphe ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Whilst several studies have investigated the role of serotonergic receptor subtypes in learning and memory, relatively few studies have examined their role in attentional processes. Objective: The present study investigated the role of pre- and postsynaptic 5-HT1A receptors on rats’ attentional performance in the five-choice serial reaction time task (5-CSRT). Methods: Hungry rats were trained in the 5-CSRT task to detect brief (0.5 s) flashes of light presented randomly in one of five locations with a fixed intertrial interval of 5 s paced by the rat. We studied the effects of 8-OH-DPAT, a 5-HT1A receptor agonist, at various subcutaneous (SC) doses (10–100 µg/kg) on measures of rats’ discriminative accuracy (the index of attentional functioning) and various behavioural indices of response control and motivation. Manipulations of basic task parameters, intracerebroventricular (ICV) injections of 5,7-dihydroxytryptamine (5,7-DHT) to deplete forebrain 5-HT and treatments with a selective 5-HT1A receptor antagonist WAY 100635 were made in order to determine the behavioural and neural specificity of the effects of 8-OH-DPAT. Results: A dose of 100 µg/kg, but not lower doses, significantly reduced choice accuracy and increased errors of omission, latencies to respond correctly and to collect food reward and premature responses. All these effects were completely blocked by WAY 100635, injected SC 5 min before 8-OH-DPAT at doses from 10–100 µg/kg. WAY 100635 by itself had no effect in the task. Dimming the visual stimuli to one-third of the usual brightness did not modify the effect of 8-OH-DPAT on choice accuracy. Prolonging the stimuli from 0.5 to 1.0 s reversed 8-OH-DPAT’s effect on choice accuracy but did not modify the other effects on rats’ performance. An ICV injection of 150 µg 5,7-DHT, which depleted forebrain serotonin by 90%, reversed 8-OH-DPAT’s effect on choice accuracy but did not modify the effects on errors of omission and latency to make correct responses. Similar effects were found by infusing 1.0 µg/0.5 µl WAY 100635 in the dorsal raphe 5 min before 8-OH-DPAT. 8-OH-DPAT increased the latency to collect the reinforcement; this effect was attenuated by ICV 5,7-DHT and completely antagonized by WAY 100635 in the dorsal raphe. Rats treated with 5,7-DHT or 8-OH-DPAT showed more premature responses and these effects were markedly reduced by the combined treatment. Conclusions: The results suggest that stimulation of presynaptic 5-HT1A receptors is involved in the ability of 8-OH-DPAT to cause attentional dysfunction and enhance impulsivity while slowing of responding and increase in errors of omission mainly depend on stimulation of postsynaptic 5-HT1A receptors.
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  • 37
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    Urological research 28 (2000), S. 141-146 
    ISSN: 1434-0879
    Keywords: Key words Kidney ; Nitric oxide ; Ischemia-reperfusion injury ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In this study we attempted to clarify the release of nitric oxide (NO) and its role in the ischemia-reperfusion rat kidney. After right nephrectomy, male Wistar rats were divided into four groups: one sham operated and three groups who underwent ischemia (30 min) and reperfusion of the left renal artery. Thirty minutes prior to ischemia-reperfusion, two groups were injected intraperitoneally with 10 and 30 mg/kg of NG-nitro-l-arginine methylester (L-NAME). Real-time monitoring of blood flow and NO release in the rat kidney was measured with a laser Doppler flowmeter and an NO-selective electrode, respectively. Serum creatinine and blood urea nitrogen (BUN) levels were measured 1 and 7 days after the induction of ischemia-reperfusion. Clamping of the renal artery decreased blood flow to 1–5% of the basal level measured before clamping. After removal of the clip, the blood flow of the 30 mg/kg L-NAME rats was significantly lower than that of the controls. Immediately following the clipping of the renal artery, NO release rapidly increased. After removing the clip, NO release immediately returned to three-quarters of the basal level. Serum creatinine and BUN levels of the ischemia-reperfusion rats were slightly but not significantly higher and those of 30 mg L-NAME rats were significantly higher than those of the control or ischemia-reperfusion rats 1 day and 7 days after ischemia-reperfusion. Our data suggest that NO acts as a cytoprotective agent in ischemia-reperfusion injury of the rat kidney.
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  • 38
    ISSN: 1434-0879
    Keywords: Key words Castration ; Epidermal growth factor ; Insulin-like growth factor I ; Prostate ; Testosterone ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) are strong inducers of proliferation to prostate cells cultured in serum-free medium. Accordingly we wanted to study the growth of the prostate gland in castrated rats after treatment with EGF, IGF-I and testosterone. Castrated Wistar rats were treated with growth factors (EGF 35 μg/rat per day; IGF-I 350 μg/rat per day) or testosterone (2 mg/rat per day) for 3 days either immediately after or 10 days after castration. Prostate tissue was examined by stereological and immunohistochemical techniques and by enzyme-linked immunosorbent assay (ELISA). Treatment with EGF inhibited the involution of the prostate (P 〈 0.05), whereas treatment with IGF-I did not affect the prostate involution as compared to castrated controls. EGF treatment significantly increased the endogenous rat EGF in the ventral prostate, but cellular proliferation was not affected. Testosterone treatment increased the weight of the prostate, by increase of all tissue components of the prostate, and significantly increased cellular proliferation. Systemic administration of EGF but not IGF-I decreased the involution of the rat prostate induced by castration. Compared with testosterone, the effects of EGF treatment on the prostate involution were moderate, and the effects of EGF were not related to cellular proliferation.
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  • 39
    ISSN: 1434-0879
    Keywords: Key words Bladder ; Rat ; Aging ; Obstruction ; Cystometrics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Bladder dysfunction in the aging population is a significant problem. However the concomitant presence of other diseases in many patients can make it difficult to distinguish between changes in bladder function and other influences. The present study was designed to study, in aging rats, bladder function and the effect of partial bladder outlet obstruction (BOO) on bladder function. Cystometrics were performed in awake, female Fischer 344 rats of four age groups (6, 12, 18 and 24 months) following subcutaneous implantation of a mediport catheter. Cystometric evaluations were carried out in control rats or those subject to three weeks of BOO. Bladder compliance significantly decreased with aging, which reflected an increase in threshold pressure without changes in bladder capacity. Partial BOO caused development of severe bladder instability. Following BOO, bladder capacity and compliance were significantly increased in all age groups. Threshold pressure was lower in obstructed animals, except for 6-month rats. Younger animals were able to generate a higher contraction pressure to compensate for the BOO, whereas older animals did not. Using an awake model of cystometric measurement, we have demonstrated that aging, by itself can affect bladder function. Furthermore, aged animals respond differently to BOO than younger animals. These results demonstrate that both aging and disease can contribute to bladder dysfunction, and suggest that treatment of bladder dysfunction may require a combination of therapies targeted to multiple etiologies.
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  • 40
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    Child's nervous system 16 (2000), S. 451-456 
    ISSN: 1433-0350
    Keywords: Keywords Intracranial pressure ; CSF dynamics ; Infusion test ; Rat ; H-Tx rat ; Outflow resistance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Although the hydrocephalic H-Tx rat is a widely used model, data on the cerebrospinal fluid (CSF) dynamics in hydrocephalic rats are rare or – as the pressure volume index (PVI) – not available. We used hydrocephalic and nonhydrocephalic H-Tx rats, a stock with a high percentage of inherited hydrocephalus, for the evaluation of such data. In addition, a new, simple mathematical algorithm (”dynamic infusion test”), which has not formerly been used in animal experiments, was used as a pathophysiological model of CSF dynamics. Compared with classical methods for evaluation of these data, the dynamic infusion test gives a deeper insight into the relation between ICP and CSF dynamics. It was found that the resistance to outflow (ROF) in hydrocephalic rats was at least twice that in nonhydrocephalic rats. The PVI measured was similar in hydrocephalic and nonhydrocephalic animals, but clearly higher than the values reported in the literature. This may be attributable to the fact that the classically used bolus test, in contrast to the ”dynamic infusion test”, is representative only for the CSF compartment which is directly exposed to the bolus application.
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  • 41
    ISSN: 1432-2277
    Keywords: Key words Small bowel transplantation ; Monoclonal antibody ; Rat ; Rejection ; Flow cytometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This study assessed the effect of an anti-rat CD4 monoclonal antibody (OX38) on heterotopic small bowel allograft rejection. Fully allogeneic small bowel transplants were performed in the PVG-to-DA-rat strain combination. Animals received either i) short course (days –1, 0 and 1) of 1 mg/kg per day OX38, ii) short course of 5 mg/kg per day or iii) extended course (days –2, –1, 0, 1, 2 and twice weekly thereafter) of 1 mg/kg per day. Both the high dose (13 days) and extended low-dose (12 days) courses prolonged graft survival compared to untreated control animals (7 days). The low-dose, short-course treatment had no effect. Similar regimens were given to animals that did not receive transplants and in which peripheral blood CD4+ cell counts fell to between 20 and 55 % of pretreatment levels and 20–30 % of binding sites were blocked. In summary, anti-CD4 monoclonal antibody therapy delayed rejection of rat small bowel allografts; however, long-term survival was not achieved.
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  • 42
    ISSN: 1432-2307
    Keywords: Keywords 7 ; 12-dimethylbenz(a)anthracene ; Rat ; Submandibular gland ; Adenocarcinoma Myoepithelial cell
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  In an attempt to induce adenocarcinoma containing myoepithelial cells (MECs) in the rat submandibular gland, we injected 7,12-dimethylbenz(a)anthracene (DMBA) dissolved in acetone into the glands of rat pups at the age of 10 days. In both male and female pups, the glands, including their developing terminal secretory units, contained far greater numbers of cells positive for proliferating cell nuclear antigen (PCNA) than did adult glands. A single administration of 1% DMBA (0.05 ml/130 g b.w.) did not produce adenocarcinoma, but did induce occasional sarcomas, such as rhabdomyosarcoma and fibrosarcoma, in 2 months. Most glands regenerated with minimal scar formation. Microscopically, these glands were atypical in that they contained increased numbers of PCNA-positive cells, underdeveloped granular ducts, and striated ducts surrounded by MECs positive for alpha smooth muscle actin (αSMA). Though these features were also observed in the regenerated glands after acetone injection, the number of PCNA-positive cells was relatively high in the glands of DMBA-treated females, especially in the terminal secretory unit. The second DMBA injection at 10 weeks of age produced adenocarcinoma made up of αSMA-positive MECs and keratin 19-positive duct cells. Such MEC-associated adenocarcinoma was induced in the glands of more than half the female but not the male animals. Replacement of either of the double DMBA treatments with acetone, or DMBA treatment, single or double, of adult glands did not produce adenocarcinoma, but did produce sarcoma and squamous cell carcinoma. These results suggest that (1) at least two genetic mutations are necessary for induction of adenocarcinoma with MECs in the rat submandibular gland, (2) the mutation is efficiently introduced to pup glands whose terminal secretory units exhibit extreme proliferative activity, and (3) the second mutation is difficult to introduce in male glands, whose proliferative activity is relatively low, and/or transformed cells need some female hormone after the mutation to propagate.
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  • 43
    ISSN: 1432-2277
    Keywords: Key words Small bowel transplantation ; Split tolerance ; FK 506 ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Functional long-term allograft survival after experimental small bowel transplantation (SBT) is limited by chronic rejection. Initial application of high-dose FK 506 has been shown to induce stable long-term graft function. In order to examine whether this long-term function is associated with donor-specific tolerance, we analyzed the functional status of recipient T cells in vivo and in vitro. One-step orthotopic SBT was performed in the allogeneic Brown Norway (BN)-to-Lewis rat strain combination. FK 506 was given daily at a dose of 2 mg/kg from days 0–5 in the rejection model and from days 0–9 in the long-term functional model. Mean survival time in the rejection model was 98 ± 2.8 days. Histological examination of these small bowel allografts disclosed signs of chronic rejection. In contrast, all animals of the long-term functional model survived long term ( 〉 250 days) without clinical signs of chronic rejection. The latter model, furthermore, produced evidence of donor-specific tolerance. Whereas heterotopic Dark Agouti (DA) hearts were rejected regularly within 7 days, BN hearts survived indefinitely ( 〉 70 days). In vitro, mixed leukocyte reactivity of CD4 + T cells was similarly strong against donor (BN) antigens as against third-party (DA) antigens. The split tolerance revealed by our in vivo and in vitro results enabled acceptance of both the small bowel allograft without signs of chronic rejection and of donor-specific heart allografts.
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  • 44
    ISSN: 1432-2277
    Keywords: Key words Implantation model ; Aortic valves ; Valve dysfunction ; Rejection ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Structural failure of heart valve allografts may be related to technical factors or immunological reactions. To circumvent nonimmunological factors a new rat implantation model was developed to study whether alloreactivity results in histopathological changes and valve dysfunction. Syngeneic (WAG-WAG, DA-DA) and allogeneic (WAG-BN, WAG-DA) transplantation was carried out using this new technique, and the function of explanted valves was assessed 21 days later by retrograde comptence testing. Additionally, grafts were examined using standard histological and immunohistochemical techniques. There was no leakage during retrograde injection in nine of tem syngeneic and two of ten allogeneic grafts. Microscopically, syngeneic valves appeared normal without fibrosis or intimal thickening, although CD8+ lymphocytes and macrophages were found in necrotic myocardial rim and adventitia. In contrast, allogeneic valves were deformed and noncellular, with extensive infiltration of CD4+, CD8+ and CD68+ cells in adventitia and media. Absence of fibrosis and intimal thickening in syngeneic transplanted valves indicated circumvention of nonimmunological factors. Allogeneic valve transplantation induces cellular infiltration in the graft with subsequent graft failure.
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  • 45
    ISSN: 1432-2277
    Keywords: Key words Hypoxia-reoxygenation ; JNK1/SAPK1 ; Rat ; Hepatocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Organ injury after ischemia and reperfusion (I/R) remains one of the most important limiting factors in liver surgery and transplantation. Oxygen-free radical (OFR) generation is considered a major cause of this damage. JNK1/SAPK1, a member of MAPK family, regulates cell adaptation to stressful conditions. The aim of this study was to determine if hypoxia-reoxygenation (H/R) can activate JNK1/SAPK1 and if OFR are involved in this activation. Primary cultured rat hepatocytes isolated from other liver cells and blood flow were submitted to warm and cold H/R phases mimicking surgical and transplant conditions. JNK1/SAPK1 was activated by both warm and cold H/R. Deferoxamine (1 mM), di-phenyleneiodonium (50 μM) and N-acetylcysteine (10 mM) significantly inhibited this kinase activation.
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  • 46
    ISSN: 1432-2277
    Keywords: Key words Kidney transplantation ; Rat ; Chronic rejection ; Cytomegalovirus ; Adhesion molecules
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Previous studies have demonstrated that both cytomegalovirus (CMV) infection and prolonged cold ischemia of the allograft (CI) are associated with chronic rejection of renal transplants. The purpose of this study is to investigate the effect of CMV infection, of CI and of the combination of both, on the progression of chronic rejection, and to obtain a more detailed insight in their effects on the expression of adhesion molecules. Therefore, a rat transplantation model was used. Lewis recipients of renal allografts (with and without CI) from MHC-incompatible Brown Norway rats were inoculated with rat CMV or left uninfected. CMV infection alone resulted in an increased influx of CD4+ cells and macrophages early after infection, and in an increase in glomerular sclerosis and intima proliferation. CI caused an increase in infiltrating NK cells and an effect on intimal proliferation, glomerular sclerosis, and tubular atrophy. When CMV infection and CI were combined, an additive effect could be measured. This was however not the case for the function of the kidney. The creatinin showed a synergistic effect of the two influencing factors. Due to the CMV infection, an increase in CD49 d cells was detected. CI resulted in an increase in CD18 cells and an increase in the expression of CD62P on vessels, and CD54 and CD44 on tubules. When CMV infection and CI were combined, all the effects caused by CMV and CI alone were present in an additional way.¶The results of the present study suggest that special attention should be paid to the recipient of an ischemically injured graft when either the donor or the recipient is CMV-infected. The patterns seen in histology, the infiltration of leukocytes and the expression of adhesion molecules, suggest that CI and CMV infection both have an effect on rejection, but act by different mechanisms.
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  • 47
    ISSN: 1432-2307
    Keywords: Key words T-type calcium channel blockade ; Mibefradil ; Myocardial infarction ; Cardiac remodeling ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Fibrillar collagen accumulates within the interstitium and around coronary arteries following cardiac failure and is responsible for abnormal myocardial stiffness and reduced coronary performance associated with impaired cardiac function. The aim of the study was to determine the effects of long-term treatment with the T-type calcium channel antagonist mibefradil on myocardial remodeling and cardiac function after chronic myocardial infarction (MI). MI was induced by permanent ligation of the left coronary artery in male Wistar rats. Animals were assigned to sham-operated, placebo-treated or mibefradil-treated (10 mg/kg per day p.o.) MI groups. Treatment with mibefradil was started either 7 days before, 24 h after, or 7 days after ligation and continued for 6 weeks after MI. At this time point, mean arterial blood pressure (MAP), heart rate (HR), left ventricular end-diastolic pressure (LVEDP) and cardiac contractility (dP/dtmax) were measured in conscious rats. Morphometric parameters were determined in picrosirius red-stained hearts: total heart weight (THW), interstitial and perivascular collagen volume fraction (ICVF, PCVF), myocardial infarct size (IS), vascular perimeter (VP), inner vascular diameter (IVD) and media thickness (MT). Six weeks after MI, MAP and dP/dtmax were decreased, and LVEDP was increased in placebo-treated animals. In mibefradil-treated animals whose treatment started 7 days before or 24 h after MI, MAP and dP/dtmax were higher, and LVEDP was lower than in placebo-treated controls. THW, ICVF, PCVF and MT were higher in placebo-treated animals. Mibefradil treatment resulted in higher ICVF and IS, higher VP and IVD (when started 7 days before MI) and lower PCVF and MT (when started 7 days before or 24 h after MI) than were observed in placebo-treated controls. Chronic treatment with mibefradil reduced interstitial and perivascular fibrosis and improved cardiac function in MI-induced heart failure in rats. Cardiac remodeling was best prevented when treatment was begun before the ischemic event.
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  • 48
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    Psychopharmacology 148 (2000), S. 106-110 
    ISSN: 1432-2072
    Keywords: Key words Interferon ; Depression ; Forced swimming test ; Locomotor activity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Objectives: We examined the immobility of the forced swimming test induced in an animal model by human interferon (IFN), which has often been reported to induce depression in clinical use. Methods: In the present study, we examined the effects of human IFNs on results of the forced swimming test in rats. Results: Single intravenous (IV) administration of human IFN-α (6×104 IU/kg), but not of human IFN-β or -γ, significantly increased immobility time in the forced swimming test in rats. Repeated administration of human IFN-α (6×103 IU/kg) also significantly increased the immobility time. On the other hand, none of the rat IFNs (rat IFN-α, -β and -γ, 6×104 IU/kg, IV) changed the immobility time. Neither human IFNs nor rat IFNs changed the locomotor activity of rats. Conclusions: These findings suggest that human IFN-α has a greater potential for inducing increase of the immobility in the rat forced swimming test than human IFN-β and -γ, and that the effect of human IFN-α might not be mediated through IFN-α/β receptors.
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  • 49
    ISSN: 1432-2072
    Keywords: Key words Opiate receptor ; Antinociception ; Habituation ; Novelty ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: There is now extensive evidence demonstrating that exposure to novel stimuli induces hypoalgesia and that this effect habituates over repeated exposure to the stimuli. Moreover, it has been shown that administration of the nonselective opiate receptor antagonist naloxone can attenuate the rate of habituation of novelty-induced hypoalgesia. Objectives: The present experiments were conducted to determine the relative influence of different opiate receptor subtypes in the attenuation of the habituation of novelty-induced hypoalgesia. Methods: In experiments 1–3, different groups of male, Wistar rats (275–300 g) were administered vehicle, 0.5, 1.0 or 2.0-nmol doses of the µ-selective antagonist Cys2-Tyr3-Orn5-Pen7-amide (CTOP), the δ-receptor selective antagonist naltrindole, or the κ-selective antagonist nor-binaltorphimine (nor-BNI). In experiment 4, animals were administered vehicle, 5, 25 or 75-nmol doses of nor-BNI. All injections were delivered to the right lateral ventricle 30 min prior to exposure to a novel hot-plate apparatus (48.5°C), once a day for eight consecutive days. Results: Paw-lick latencies in vehicle-treated animals were long during the initial exposures and declined over repeated tests, suggesting the habituation of novelty-induced hypoalgesia. The rate of habituation was significantly attenuated by administration of 1.0-nmol and 2.0-nmol doses of CTOP, by a 2.0-nmol dose of naltrindole, but was unaffected by all doses of nor-BNI. Conclusions: These results support the involvement of the µ and δ, but not the κ, opiate receptor subtypes in the habituation of novelty-induced hypoalgesia.
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  • 50
    ISSN: 1432-2072
    Keywords: Key words Benzodiazepine ; Operant ; Force ; Tolerance ; Chronic ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: Several benzodiazepines (BZs) have been shown to increase the peak force of operant responses at doses that increased, decreased, or had no effect on response rate, suggesting that operant response force may be a sensitive index of BZs’ effects rather than solely a correlate of rate-dependent effects. In addition, contingent tolerance to the rate-dependent effects of BZs has been reported, but the degree of contingent tolerance that develops when the critical variable of the task is force of the response has not been explored. Objectives: These experiments examined the effects of acute and repeated oral administration of diazepam (DZ) and midazolam (MZ) on a force-differentiation task to explore the importance of task requirements on the development of contingent tolerance. Methods: Two groups of rats were trained to press a force-sensing operandum, and responses having peak forces falling within fixed lower and upper limits [low force (8–10 g) or high force (40–50 g)] were reinforced with water. Acute effects of the oral administration of DZ (0.3, 1.0, 3.0, 10.0, 30.0 mg/kg) and MZ (same doses) were determined for the discriminated-force task before and after a repeated-administration procedure. Results: When administered acutely, both drugs increased the peak force of responses in a dose-related manner and concomitantly reduced the proportion of reinforced responses, with MZ exhibiting greater potency. For the next 36 days, one group received drug before experimental sessions and the other group received drug after the experimental session. A second dose–effect determination demonstrated that rats chronically dosed with DZ or MZ pre-session displayed more contingent tolerance to alterations in peak force than rats that had received 36 drug injections post- session, where there was no opportunity to practice the force-discrimination response while under the drug state. Conclusions: These results suggest that perceptual motor difficulty of the task rather than effort may be an important variable in predicting the degree of contingent tolerance that develops. Additionally, these results suggest that both behavioral and pharmacological mechanisms are involved in the development of drug tolerance to the BZs.
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  • 51
    ISSN: 1438-8359
    Keywords: Key words: Halothane ; Dopamine release ; Dopamine uptake ; Microdialysis ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose. In our previous microdialysis study, sevoflurane or isoflurane anesthesia significantly decreased the extracellular level of dopamine in rat striatum in vivo. On the other hand, other investigators demonstrated that halothane anesthesia either increased or did not affect the extracellular dopamine level. To explore the differences among these volatile anesthetics, the effects of halothane and nitrous oxide on the striatal dopamine level were reinvestigated. Methods. Halothane alone, nitrous oxide with or without halothane, or drugs known to affect the dopaminergic pathway were administered to rats. Microdialysates were collected every 20 min and directly applied to an on-line high-performance liquid chromatograph without any pretreatment. The effects of halothane on respiratory and cardiovascular variables were monitored. Results. General anesthesia with halothane alone de-creased the dialysate (extracellular) concentration of dopamine but increased that of dopamine metabolites. Nitrous oxide alone slightly increased dopamine metabolites in dialysates but did not affect the halothane-induced decrease in extracellular dopamine. Apomorphine and haloperidol reproduced reported results, confirming the adequacy of our methodology. Nomifensine- or methamphetamine-induced increase in extracellular dopamine was augmented by halothane. Conclusion. These results suggest that halothane po-tently enhances striatal dopamine release and activates the reuptake or metabolic process, which is consistent with our previous results for sevoflurane or isoflurane. Volatile anesthetics interfere with dopamine regulation, at least in the rat striatum.
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  • 52
    ISSN: 1530-0358
    Keywords: Pravastatin ; ras p21 isoprenylation ; Colon carcinogenesis ; Flat colon tumor ; Azoxymethane ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract PURPOSE: The effect of pravastatin, an inhibitor ofras p21 isoprenylation, on the gross type of colon tumors induced by azoxymethane was investigated in Wistar rats. METHODS: Rats received ten weekly subcutaneous injections of 7.4 mg/kg body weight of azoxymethane and intraperitoneal injections of 10 or 20 mg/kg body weight of pravastatin every other day until the end of the experiment at Week 45. RESULTS: Administration of pravastatin at both dosages had no significant effect on the incidence of colon tumors but significantly increased the incidence of rats with adenomas only. In contrast to the elevated adenomas in control rats, flat adenomas were significantly more prevalent in rats given pravastatin. Pravastatin at both doses significantly decreased the labeling index, but not the apoptotic index, of elevated adenomas, whereas it significantly decreased the labeling index but increased the apoptotic index of flat adenomas. Administration of pravastatin at both dosages also significantly decreased the amounts of membrane-associatedras p21 in colon tumors. CONCLUSIONS: These findings suggest that theras oncogene may be closely related to the development of adenocarcinomas from adenomas and the development of elevated or polypoid tumors of the colon.
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  • 53
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    Medical & biological engineering & computing 38 (2000), S. 42-48 
    ISSN: 1741-0444
    Keywords: Bowel sounds ; Rat ; Motility ; Body acoustics ; Signal detection ; Signal characterisation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract This study is aimed at detecting gastrointestinal sounds (GIS) and correlating their characteristics with gastrointestinal (GI) conditions. The central hypotheses are that GIS generation depends on the motility patterns and the mechanical properties of the gut, and that changes in those result in measurable differences in GIS. An animal model which included both healthy rats and those with small bowel obstruction (SBO) was developed. The acoustic bursts, of GIS were detected by amplitude thresholding the signal envelope. Three methods of envelope estimation were proposed and evaluated. Envelope estimation using a Hilbert transform was found to produce the best results in the current application. The duration and dominant frequency of each detected GIS event was estimated and clear differences between healthy and diseased rats were discovered. In the control state, GIS events were found to consistently be of relatively short duration (3–65ms). Although the majority of events in the SBO state had similar short duration, infrequent longer events were also detected and appeared to be pathognomonic. Long duration events (〉100 ms) occurred in each of seven obstructed, but in none of 14 non-obstructed, cases (p〈0.001). It is concluded that GIS analysis may prove useful in the non-invasive, rapid, and accurate diagnosis of SBO.
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  • 54
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    Annals of biomedical engineering 28 (2000), S. 128-134 
    ISSN: 1573-9686
    Keywords: Hippocampus ; Vigilance states ; Paired-pulse ; Dentate gyrus ; Dentate granule cells ; Evoked response ; Rat ; In vivo studies ; Perforant path ; Maturation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Technology
    Notes: Abstract This study examined the effect of normal development and vigilance state on the modulation of dentate granule cell activity in the freely moving rat at 15, 30, and 90 days of age across three vigilance states: quiet waking, slow-wave sleep, and rapid eye movement sleep. Using paired-pulse stimulation, the paired-pulse index (PPI) was obtained for the dentate evoked field potentials elicited by the stimulation of the medial perforant path. Although significant differences in PPI values were observed during development, no significant vigilance state related changes were obtained. Preweaning infant rats, i.e., 15-day old, exhibited significantly less early (interpulse intervals, IPI= 20–50 ms) and late (IPI = 300–1000 ms) inhibition, and less facilitation (IPI = 50–150 ms) when compared to the 90-day old adult rats during all three vigilance states. PPI values obtained from the 30-day old group fell intermediate between the 15- and 90-day old animals. These changes in PPI values provide a quantitative measure of changes in the modulation of dentate granule cell excitability during normal maturation. They can now can be used to evaluate the impact of various insults, such as prenatal protein malnutrition or neonatal stress, on hippocampal development. © 2000 Biomedical Engineering Society. PAC00: 8717Nn, 8719La, 8719Nn
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  • 55
    ISSN: 1573-9686
    Keywords: Heart ; Left ventricle ; LV contractility ; ESPVR ; Pig ; Rat ; Magnetic resonance imaging
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Technology
    Notes: Abstract The end systolic pressure–volume relation (ESPVR) has been shown to be a relatively load independent measure of left ventricular (LV) contractility. Recently, several single-beat ESPVR computation methods have been developed, enabling the quantification of LV contractility without the need to alter vascular loading conditions on the heart. Using a single-beat ESPVR method, which has been validated previously in humans and assumes that normalized elastance is constant between individuals of a species, we studied the effects of myocardial infarction on LV contractility in two species, the rat and the pig. In our studies, LV pressure was acquired invasively and LV volume determined noninvasively with magnetic resonance imaging, at one week postinfarction in pigs and at 12 weeks postinfarction in rats. Normalized systolic elastance curves in both animal species were not statistically different from that of humans. Also, the slope of the ESPVR $$\left( {E_{es} } \right)$$ decreased significantly following infarction in both species, while the volume-axis intercept $$\left( {V_0 } \right)$$ was unaffected. These results indicate that a single-beat ESPVR method can be used to measure the inotropic response of the heart to myocardial infarction, and that the basis for this method (i.e., constant normalized elastance) is applicable to a variety of mammalian species. © 2000 Biomedical Engineering Society. PAC00: 8719Uv, 8761Lh, 8719Hh, 8719Rr, 8719Ff
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  • 56
    ISSN: 0219-1032
    Keywords: c-Fos ; Dopamine ; D1 ; Hippocampus ; Rat ; Synaptic Plasticity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract While dopamine is likely to modulate hippocampal synaptic plasticity, there has been little information about how dopamine affects synaptic transmission in the hippocampus. The expression of IEGs including c-fos has been associated with late phase LTP in the CA1 region of the hippocampus. The induction of c-fos by dopaminergic receptor activation in the rat hippocampus was investigated by using semiquantitative RT-PCR and immuno-cytochemistry. The hippocampal slices which were not treated with dopamine showed little expression of c-fos mRNA. However, the induction of c-fos mRNA was detected as early as 5 min after dopamine treatment, peaked at 60 min, and remained elevated 5 h after treatment. Temporal profiles of increases in c-fos mRNA by R(+)-SKF-38393 (50 μM) and forskolin (50 μM) were similar to that of dopamine. An increase in [cAMP] was observed in dopamine-, SKF-, or forskolin-treated hippocampal slices. By immunocytochemical studies, control hippocampal cells showed little expression of c-Fos immunoreactivity. However, when cells were treated with dopamine, an increase in the expression of c-Fos immunoreactivity was observed after treatment for 2 h. The treatment of hippocampal neurons with R(+)-SKF38393 (50 μM) or forskolin (50 μM) also induced a significant increase in c-Fos expression. These results indicate that the dopamine D1 receptor-mediated cAMP dependant pathway is associated with the expression of c-Fos in the hippocampal neurons. These data are consistent with the possible role of endogenous dopamine on synaptic plasticity via the regulation of gene expression. Furthermore, these results imply that dopamine might control the process of memory storage in the hippocampus through gene expression.
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  • 57
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    Annals of biomedical engineering 28 (2000), S. 1101-1115 
    ISSN: 1573-9686
    Keywords: Time–frequency analysis ; Coherence ; Cross correlation ; Nonstationary persistent signals ; Central pattern generator ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Technology
    Notes: Abstract We present a novel time-varying phase spectrum (TVPS) method to quantify the dynamics of coevolution of two persistent nonstationary coupled signals. Based on the TVPS, an instantaneous intersignal phase shift is defined within the primary frequency range in which the two signals are highly correlated. The TVPS is estimated using a fixed-window method or an adaptive-window method. In the latter method, the window length changes dynamically and automatically as a function of change in frequency of the signals. The effects of altering window types and lengths on the accuracy of the estimation of the primary phase shift is assessed by analyzing synthesized linear chirp signals with decaying amplitude and constant relative phase shift or decaying amplitude and changing relative phase shifts. The methods developed are also used for determining the evolution of the primary phase shift among ventral root activities during fictive locomotion in an in vitro rat spinal cord preparation. The analyses indicate that the TVPS method in conjunction with the determination of the primary frequency range, allows determination of both the evolution of the coupling strength and the evolution of the phase shift between two persistent nonstationary rhythmic signals in the joint time–frequency domain. An adaptive window reduces the estimation bias and the estimation variability. © 2000 Biomedical Engineering Society. PAC00: 0230-f, 8780Tq
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  • 58
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    European journal of applied physiology 83 (2000), S. 310-319 
    ISSN: 1439-6327
    Keywords: Key words Motor unit ; Mechanomyography ; Evoked contraction ; Medial gastrocnemius muscle ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Acoustic phenomena accompanying contractions of single motor units (MUs) have previously received little attention. Therefore, in the present study, the mechanomyographic (MMG) signals during evoked contractions of single MUs have been recorded from the medial gastrocnemius muscle of the rat. A piezoelectric transducer immersed in a paraffin-oil pool was used for the measurement of these signals. Muscle fibre action potentials, tension and MMG were recorded in parallel during twitch (the weakest) and fused tetanic (the strongest) MU contractions. It was observed that the onset of the MMG signals was coincident with the beginning of the increase in tension for both the twitch and tetanus. Weaker MMG signals than those accompanying the beginning of the first phase of the fused tetanus were seen during the beginning of the relaxation after tetanic contraction. During contraction and relaxation, MMG signals were characterised by the reverse-direction of the first extreme phase, positive and negative, respectively. No MMG signals were observed when the tension was constant during the fused tetanus. The amplitude of MMG signals was correlated with both the tension increase and the velocity of tension increase during both the twitch and the fused tetanus. The strongest MUs (fast fatiguable) generated MMG signals of the highest amplitude. MMG signals were not detected for some of the weakest slow MUs (with tension increases of ≤2 mN). These results indicate a strong correlation between the MMG and the change of tension. Therefore, we believe that MMG signals are generated by muscle deformation that occurs during the contraction of MU muscle fibres. We conclude that the number of active muscle fibres, their topography, and their localisation in relation to the muscle surface (which is variable for different types of MUs) influence these MMG phenomena.
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  • 59
    ISSN: 1615-3146
    Keywords: Key Words Spinal cord compression ; Autoradiography ; Blood flow ; ATP ; Glucose ; Lactate ; Bioluminescence ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Many data are available concerning spinal cord blood flow (SCBF) and metabolism on various models and timing after spinal cord injury, however, detailed information on their exact relationship in the same injury model is lacking. This relationship is a crucial factor in the understanding of the pathophysiology of spinal cord trauma. Rats were subjected to lumbar laminectomy or lumbar spinal cord compression trauma. 3 hours later, changes in SCBF were evaluated autoradiographically and changes in ATP, glucose and lactate levels were analyzed using substrate-specific bioluminescence techniques. Measurements were performed at the lesion site (segment L4), adjacent segments (L3 and L5) and at remote thoracic segments (Th8 to Th9). Laminectomy alone did not change SCBF, both in thoracic and lumbar segments. In contrast, ATP levels were significantly reduced and lactate levels were increased at the lesion site and in adjacent lumbar segments at 3 hours after laminectomy, whereas glucose levels were not significantly changed. In animal subjected to additional compression trauma, SCBF was significantly reduced in segments L3, L4 and L5 paralleled by a significant ATP reduction and lactate increase. Glucose levels did not differ significantly from controls 3 hours after compression injury. This metabolic profile was also reflected in the remote thoracic segments. In contrast, SCBF was not reduced in thoracic segments of traumatized animals. The observation that ATP was already significantly reduced and lactate increased in laminectomized segments and in remote thoracic regions after trauma signals that metabolic changes are sensitive indicators to spinal stress. The fact that posttraumatic metabolic profile differs from the pattern of hemodynamic and metabolic changes induced by ischemia, suggests posttraumatic mediators may be involved in the different regulation of the energy producing machinery.
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  • 60
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    Anatomy and embryology 145 (1974), S. 169-186 
    ISSN: 1432-0568
    Keywords: Renal innervation ; Rat ; Peripheral nerves ; Neuroeffector zones ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung In der Rattenniere werden die muskelzellhaltigen arteriellen Gefäße und der juxtaglomeruläre Apparat innerviert. Blutgefäße mit Pericyten, porenhaltige Capillaren sowie die Tubuli der Rinde und des Markes werden nicht von Nervenfasern begleitet. Ganglienzellen wurden in der Rattenniere nicht beobachtet. Periphere Nerven mit einem ein-bis zweischichtigen Perineurium kommen im paravasalen Gewebe der Interlobar- und Arcuata-Arterien vor; sie enthalten neben zahlreichen marklosen Nervenfasern gewöhnlich auch 2–4 markhaltige. Nervenfaser-Bündel ohne perineurale Scheide finden sich im paravasalen Gewebe der Arcuata- und Interlobular-Arterien. Darüber hinaus sind in unmittelbarer Nachbarschaft der großen Arterien (Interlobar-, Arcuata- und Inter-lobular-arterien) und der Vasa afferentia marklose Nervenfasern und freie Axone vorhanden, die auch die proximalen Abschnitte der Vasa efferentia der subcapsulären und intermediären Rindenschicht begleiten. Im Nierenmark werden die juxtamedullären Vasa efferentia und die Arteriolae rectae innerviert; marklose Nervenfasern und freie Axone sind nur bis zur Außen-Innenstreifen-Grenze nachweisbar. Die Innervation der muskelzellhaltigen arteriellen Gefäße erfolgt durch aufgetriebene Axonabschnitte (Neuroeffektor-Zonen), die vorwiegend agranuläre Vesikel enthalten. Diese Strukturen liegen stets an der Grenze von Adventitia und Media bzw. Elastica externa; zwischen den glatten Muskelzellender Media wurden keine vesikelhaltigen Axonabschnitte gefunden. Als minimaler Abstand zwischen den vesikelhaltigen Axonabschnitten und den von einer Basalmembran umschlossenen glatten Muskelzellen (neuromuskuläre Distanz) wurden 600 Å gemessen. Die vorliegenden Ergebnisse werden mit den fluoreszenzmikroskopischen und histochemischen Untersuchungen über die adrenerge und cholinerge Innervation der Niere verglichen. Die sich aus diesem Vergleich ergebenden Probleme und funktionellen Konsequenzen für die Innervation der Niere sowie die Natur der cholinergen Fasern (afferente oder postganglionäre parasympathische Fasern) werden diskutiert.
    Notes: Summary The innervation of the rat kidney is defined by a system which supplies those arterial blood vessels whose walls contain smooth muscle cells and the juxtaglomerular apparatus. Vessels containing pericytes, or those vessels composed of an endothelium only, as well as the tubules of both the cortex and medulla, are not innervated. Furthermore, ganglion cells do not occur in the rat kidney. The nervous apparatus of the rat kidney consists of peripheral vegetative nerves, ensheathed by a perineurium, with 2–4 myelinated fibers running in the paravasal tissue of the interlobar and arcuate arteries, and of nerve bundles without a perineurial sheath in the paravasal tissue of the arcuate and interlobular arteries. Non-myelinated fibers and free axons occur in the immediate vicinity of the great arteries (interlobar, arcuate, and interlobular) and the vasa afferentia. Nerve fibers and free axons are also seen in the vicinity of only the proximal parts of those vasa efferentia which supply the cortical capillary plexus. The arteriolae rectae of the medulla, and their vasa efferentia, from which they arise, are innervated by non-myelinated fibers and free axons which accompany these arterial vessels only to the boundary of the outer and inner stripe of the outer zone of the medulla. The functional innervation of those vessels with smooth muscle cells results from neuro-effector zones which predominantly show agranular vesicles. These structures were never seen between the smooth muscle cells within the media; the minimum neuromuscular distance was 600 Å. The present findings are correlated with the lightmicroscopically demonstrated adrenergic and cholinergic innervation. The resultant problems and functional consequences of the innervation of the kidney, especially the nature of the cholinergic fibers (afferent or post-ganglionic parasympathetic fibers) are briefly discussed.
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  • 61
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    Anatomy and embryology 145 (1974), S. 223-226 
    ISSN: 1432-0568
    Keywords: Rat ; Liver ; Bile ducts ; Cilia ; Scanning Electron Microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Numerous cilia have been demonstrated by SEM in cells of rat perilobular and portal bile ducts and ductules. Generally these cilia appear as long, cylindrical evaginations of the plasma membrane. Some of them are so long that, curving and twisting at many points, they cross the ductal lumen. It has been suggested that they may be related to a continual mixing up and propulsion of the bile product down the biliary tree.
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  • 62
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    Anatomy and embryology 143 (1974), S. 215-222 
    ISSN: 1432-0568
    Keywords: Lung ; Stretch receptors ; Light microscopy ; Electron microscopy ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Lappenbronchien (3./6.) (Durchmesser bei mittlerer Inspirationslage 500–700 μ) von männlichen und weiblichen Wistarratten wurden licht- und elektronenmikroskopisch untersucht. Diese Bronchien entsprechen im Wandbau den mittleren Bronchioli größerer Säugetiere. Freie, verzweigte lanzettförmige Terminalfasern werden im Bindegewebe der lamina propria beschrieben. Sie sind in das elastisch muskuläre System der Bronchuswand eingebaut. Die zugehörige markhaltige afferente Nervenfaser ist verzweigt und hat einen Durchmesser von 4–6 μ. Außerdem werden efferente motorische Endigungen an der glatten Bronchialmuskulatur beschrieben. Die freien lanzettförmigen und verzweigten Terminalfasern sind möglicherweise Dehnungsrezeptoren für den Hering Breuer Reflex.
    Notes: Summary In rats the 3rd to 6th bronchi, measuring 500–700 μ in diameter during inspiration, were investigated by light and electron microscopy. The histological appearance of these bronchi is comparable to that of medium sized bronchioles of larger animals. The branched and lanceolate terminals are associated with the connective tissue of the lamina propria and the smooth muscle cell layer. In this way the terminals are bound to the myoelastic system of the bronchial wall. The myelinated afferent fiber is branched and the diameter measures about 4–6 microns. Besides afferent nerve terminals these are numerous efferent endings on the smooth muscle basement laminae. It is supposed that the described receptor represents the pulmonary stretch receptor of the Hering Breuer reflex.
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  • 63
    ISSN: 1432-0568
    Keywords: Superior cervical ganglion ; Rat ; p-Chlorophenylalanine ; 5-Hydroxytryptamine ; Catecholamine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Die Wirkung von Parachlorophenylalanin (pCPA) auf die paraganglionären Zellen und sympathischen Ganglienzellen des Ganglion cervicale superius der Ratte wurde untersucht. pCPA beeinflußt die sympathischen Nervenzellen im Ganglion cervicale superius geringgradig. Es finden sich unspezifische Veränderungen des Golgi-Apparates und der Nissl-Schollen sowie eine Zunahme von Lysosomen. Bei langdauernder Behandlung degenerieren einzelne Ganglienzellen und Nervenfasern. Die paraganglionären Zellen sind bei Kontrolltieren durch “dense core vesicles” eines einheitlichen Typs charakterisiert. Im Laufe der pCPA-Behandlung finden sich degranulierte paraganglionäre Zellen. Die Degranulation der einzelnen Zellelemente ist jedoch variabel. Bei fluorescenzmikroskopischer Untersuchung zeigt sich nach pCPA-Applikation eine Verschiebung des Fluorescenzspektrums zum grünen Bereich hin. Die bei Kontrollen deutliche Gelbkomponente nimmt nach 6–12 Tagen ab und verschwindet schließlich nach 18–20 Tagen. Es wird diskutiert, ob die fluorescenzmikroskopischen Veränderungen aufgrund einer Hemmung der Serotoninsynthese oder aufgrund einer abgeschwächten Katecholaminsynthese entstehen.
    Notes: Summary The effect of parachlorophenylalanine (pCPA) on the paraganglionic and sympathetic nerve cells of the rat superior cervical ganglion was studied. pCPA influences the sympathetic nerve cells of the cervical ganglion to minimal extent. Unspecific changes of the Golgi apparatus and of the Nissl bodies as well as an increase in the number of lysosomes occur. An extended period of treatment causes degeneration of individual ganglionic cells and nerve fibers. The paraganglionic cells in control animals are characterized by dense core vesicles of an unitary type. During pCPA treatment degranulated paraganglionic cells are to be found. The degranulation of the individual cell elements varies. Fluorescence microscopic study after pCPA application shows a shift of the fluorescence spectrum toward green. The yellow component of the control group decreases after 6 to 12 days and disappears after 18 or 20 days. It is discussed whether the fluorescence microscopic changes are due to the inhibition of serotonine synthesis or to a decrease of the catecholamine synthesis.
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  • 64
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    Anatomy and embryology 144 (1974), S. 173-186 
    ISSN: 1432-0568
    Keywords: Hippocampus ; Neurogenesis ; Autoradiography ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summay The prenatal ontogeny of the hippocampus, including the anterior continuation and induseum griseum, was examined in the rat by means of tritiated thymidine autoradiography. The neurons of the anterior continuation formed between the 16th and 18th days of embryonic development. The neurons of the induseum griseum were formed on the 16th and 17th days of gestation. The pyramidal cells of ammon's horn were formed during the 16th, 17th, 18th, and 19th days of embryogenesis but were preceded by the large interneurons of the stratum lacunosum-moleculare which formed on days 15 and 16 of embryonic life. The granule cells of the superficial layers of the stratum granulosum formed during the 20th, 21st, and 22nd days of gestation.
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    Anatomy and embryology 143 (1974), S. 185-203 
    ISSN: 1432-0568
    Keywords: Basement membrane labyrinths ; Cerebral ventricles ; Development ; Rat ; Light and Electron microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Gehirne embryonaler und neugeborener Ratten wurden im Hinblick auf die frühe Entstehung der Basalmembranlabyrinthe licht- und elektronenmikroskopisch untersucht. 1. An den Hirngefäßen embryonaler Ratten der 2. und 3. Fetalwoche kommen zwar bereits Basalmembranen vor, sub- oder interependymale Basalmembranlabyrinthe fehlen aber noch. 2. Basalmembranlabyrinthe werden mit der Perjodsäure-Bisulfit-Aldehydthionin-Methode lichtmikroskopisch ab dem 20. Tag an umschriebenen Stellen des Ventrikelsystems gefunden; elektronenmikroskopisch treten die ersten Basalmembranlabyrinthe am 12. postnatalen Tag auf. 3. Die ersten interependymalen Labyrinthe erscheinen in Erweiterung der interependymalen Spalten in der Nähe von ausgedehnten Golgifeldern. Der Labyrinthinhalt besteht aus einer feinflockigen Substanz. Diese liegt wolkenartig angehäuft gegenüber bogenförmigen Ausbuchtungen lokal verbreiterter Zellmembranen. In Ausbildung begriffene Labyrinthe zeigen eine lamelläre Gliederung. 4. Ab dem 12. postnatalen Tag treten auch an den Basalmembranen der pericapillären Zellen, in denen lichtmikroskopisch Glykoproteide nachweisbar sind, zapfenartige Duplikaturen auf. Die Zapfen sind überwiegend ependymwärts gerichtet. Verbindungen zwischen den Basalmembranzapfen und den interependymalen Basalmembranlabyrinthen werden in den ersten 30 Lebenstagen nicht gefunden. 5. Sowohl an den die interependymalen Labyrinthe begrenzenden Plasmalemmata als auch am Plasmalemm der pericapillären Zellen fallen Stachelsaumbläschen auf, deren Membran in die Zellwand eingebaut wird. Ihr Inhalt scheint in die entstehenden Labyrinthe entleert zu werden. 6. Da sich an den tubulären Enden der Doppellamellen der Dictyosomen Strukturen befinden, die den Stachelsaumbläschen morphologisch gleichen, und da im Bereich des Golgifeldes und im Cytoplasma zwischen diesem und der Zellwand zahlreiche Stachelsaumbläschen liegen, wird angenommen, daß das Material der Basalmembranlabyrinthe dem Golgiapparat entstammt und vermittels der Stachelsaumbläschen zur Zellwand transportiert wird. Bogenförmige Ausbuchtungen lokal verbreiterter Zellmembranen im Bereich entstehender Labyrinthe werden als Reste von Stachelsaumbläschen aufgefaßt, deren Membran in die Zellwand eingebaut wurde. 7. Da die phylogenetische Zunahme des Hirnmantels mit einem Verlust der langen in das Gehirn reichenden basalen Ependymfortsätze an den größten Teilen der Ventrikelwand einhergeht und niedere Tiere noch nicht über Basalmenbranlabyrinthe verfügen, wird angenommen, daß diese die Transportfunktion für Stoffe aus dem Liquor übernommen haben, die vordem nach allgemeiner Auffassung über die langen Fortsätze in das Gehirn gelangten.
    Notes: Summary The brains of embryonic and new-born rats were investigated by means of light- and electron microscopy with regard to the early formation of basement membrane labyrinths. 1. Though basement membranes are already found around the brain capillaries of embryonic rats from the 2nd week of pregnancy, sub- and interependymal basement membrane labyrinths are still absent. 2. Basement membrane labyrinths, being demonstrable for light microscopy by a periodicacid-bisulfite-aldehydethionin-method, appear around the 20th day after birth at certain places of the ventricular system. By means of electron microscopy, basement membrane labyrinths have first been detected at the 12th postnatal day. 3. The earliest interependymal basement membrane labyrinths are found in enlargements of the interependymal spaces near a distended Golgi apparatus. The contents of the labyrinths, being composed of a loose flocculent material, are of a lamellar structure. In the intercellular space the material is situated opposite bow-shaped excavations of local broadenings of cell membranes. 4. From the 12th postnatal day, plug-like duplications of basement membranes occur at the ependymal side of the pericapillar cells, which contain glycoproteids. The plugs of basement membranes are directed towards the ependymal layer. No connections between the interependymal basement membrane labyrinths and the plugs of pericapillary basement membranes exist within the first 30 days of life. 5. At the plasmalemma of ependymal cells bordering the interependymal labyrinths, and at the cell membrane of pericapillary cells, coated vesicles are to be found, which are fused with the cell membrane. The contents of these vesicles seem to be released into the developing labyrinths. 6. At the tubular ends of dictyosomes, coated vesicle-like structures can be demonstrated. In the environment of the Golgi apparatus many coated vesicles are situated; they can even be found between the Golgi apparatus and the walls of labyrinthś. Therefore the coated vesicles are considered to be transport vesicles, transporting the material which is formed in the Golgi apparatus towards the cell membrane. 7. Since the phylogenetic increase of the brain mantle is accompanied by loss of the long processes of ependymal cells that reach far into the brain, and since lower animals have no basement membrane labyrinths, it is suggested that the basement membrane labyrinths have a transport functions for material from the cerebrospinal fluid which in lower animals is assumed to be transported by the long processes of ependymal cells.
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  • 66
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    Anatomy and embryology 143 (1974), S. 255-262 
    ISSN: 1432-0568
    Keywords: Median eminence ; Neuro-vascular contacts ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The vascular surface of the external layer of the median eminence is composed of neuronal and glial processes. Neuro-vascular contacts are supposed to be necessary for the release of hypophysiotropic neurohormones. The present study confirms the hypothesis that the relative extent of neuro-vascular and glio-vascular contacts varies under different functional conditions of the tubero-hypophysial system. Morphometric analysis shows that in normal rats about 20% of the surface is lined by neuro-vascular contacts. After bilateral adrenalectomy the neuro-vascular contacts are enlarged to 40% whereas application of an extract of stalk-median eminence tissue is followed by a decrease of the neuro-vascular contacts to 15%. The implications of these results are discussed.
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  • 67
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    Anatomy and embryology 144 (1974), S. 101-122 
    ISSN: 1432-0568
    Keywords: Subcommissural organ ; Periodically structured bodies ; Vascular permeability ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Die Capillaren des Subcommissuralorgans (SCO) und deren Umgebung wurden an 38 adulten Sprague-Dawley- und an 6 adulten Wistar-Ratten nach Perfusionsfixierung im Elektronenmikroskop untersucht. Saure Mucopolysaccharide wurden mit Alcianblau und Rutheniumrot, Glykoproteide mittels der Perjodsäure-Silbermethenamin-Reaktion nachgewiesen. Der Stofftransport in den Capillaren wurde mit Meerrettichperoxidase (MRP) als Tracer untersucht. Die subcommissuralen Capillaren besitzen ein ungefenstertes, vesikelarmes Endothel, das einer einfachen, durchgehenden Basallamina aufsitzt. In der Umgebung der Capillaren finden sich neben periodisch strukturierten Körpern (PSK) vereinzelt Basallamina-Labyrinthe und regellos angeordnete kollagene Mikrofibrillen. Mit der Perjodsäure-Silbermethenamin-Reaktion lassen sich Glykoproteide im Bereich der Basallamina und der nach außen anschließenden Intercellularspalten darstellen, vereinzelt auch — teils im Bereich der Basallamina, teils ihr eng angeschlossen — Gruppen parallel angeordneter, linearer Strukturen mit einem periodischen Streifenmuster. Saure Mucopolysaccharide sind nur in der lumenseitigen Glykokalyx des Capillarendothels nachweisbar. Der Aufbau der PSK aus Kollagenfilamenten erscheint sehr wahrscheinlich. Vermutungen zur Entstehung dieser hochgeordneten Strukturen werden vorgebracht. Die Traceruntersuchungen ergeben, daß unter normalen Bedingungen in den subcommissuralen Capillaren eine Blut-Hirn-Schranke (BHS) für MRP besteht, die im Endothel lokalisiert ist. Bei einem Teil der Sprague-Dawley-Ratten ist die Barriere geschädigt und der Tracer gelangt über cytopemptische Vesikel in Basallamina und Gefäßumgebung. Der Basallamina und den PSK kommt in solchen Fällen keine besondere Schranken- oder Verteilerfunktion zu. Offenbar bewirkt bei manchen Sprague-Dawley-Ratten die MRP-Injektion über die Freisetzung von endogenen biogenen Aminen aus Mastzellen eine Schädigung der BHS, was bei Wistar-Ratten nicht eintritt.
    Notes: Summary The capillaries of the subcommissural organ (SCO) and their adjacent structures of 38 adult Sprague-Dawley rats and 6 adult Wistar rats were examined in the electron microscope after perfusion fixation. Acid mucopolysaccharides were shown by Alcian Blue and Ruthenium Red, glycoproteins were identified by the periodic acid-silver methenamine technique. Horseradish peroxidase (MRP) was used as a tracer for vascular permeability. The subcommissural organ's capillaries are characterized by an unfenestrated, continuous endothelium, showing only few vesicles; the endothelium is surrounded by a single, continuous basal lamina. Adjacent to the capillaries wall there are “periodically structured bodies” (PSK), labyrinths of the basal lamina and irregularly arranged collagen fibrils. Glycoproteins are found in the basal lamina and within the intercellular clefts; in a few cases groups of parallel arranged, periodically banded linear structures are seen within or adjacent to the basal lamina. Acid mucopolysaccharides are found within the endocapillary layer of capillaries. It seems very likely that PSK represent an atypical arrangement of collagen fibrils. The formation of these structures is discussed. Under normal conditions, MRP, after intravenous injection, does not enter the perivascular space surrounding the capillaries of the SCO. A blood-brain barrier exists at the level of the capillary endothelium. In a few Sprague-Dawley rats MRP seems to alter the permeability of the capillaries. Reaction product of MRP is found within endothelial vesicles and the adjacent structures. It appears that the basal lamina and the PSK are not involved in the barrier mechanism or regulation of transport. In Sprague-Dawley rats intravenous injection of MRP seems to alter the blood-brain barrier by release of endogenous biogenic amines associated with mast cell degranulation. This effect is not observed in Wistar rats.
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  • 68
    ISSN: 1432-0568
    Keywords: Motor nerve terminals ; Methylene blue stain ; Hindlimb muscles ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary With methylene blue stain, three morphological types of motor nerve terminals were distinguished in hindlimb muscles (extensor digitorum longus, semitendinosus, soleus, and tibialis anterior muscles) of rat. Type A terminals possess many long thin branches with numerous minute swellings, type C ones possess few and thick terminal branches with few large swellings, and type B ones possess intermediate characteristics. The frequencies of occurrence of these types are characteristic for each muscle and differ between different hindlimb muscles. Specifically, soleus muscle contains a much higher proportion of type B terminals than other hindlimb muscles, and the superficial part of tibialis anterior muscle contains a higher proportion of type A terminals and a lower proportion of type C ones than the deep part. The frequencies of occurrence of types A, B, and C terminals closely parallel the frequencies of “white”, “intermediate”, and “red” muscle fibers (as determined by a fat stain), respectively, in the different muscles. As also suggested previously for the diaphragm, it is concluded that three morphological types of motor nerve terminals each may innervate one of three types of muscle fibers.
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  • 69
    ISSN: 1432-0568
    Keywords: Pantothenic acid deficiency ; Corticotropin-releasing factor ; Corticoids ; Histologie ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the outer layer of the rat median eminence “Gomori-positive” granules occur which are assumed to be the morphological correlate of the corticotropin-releasing factor (CRF). The present study was carried out in order to establish whether the amount of these CRF-granules is influenced by a pantothenic acid (PA)-deficiency, which is known to result in an inhibition of corticosteroid production. Female SPF Wistar rats were used. PA-deficiency was induced by PA-free nutrition and/or administration of the PA-antagonist Ω-methyl-PA. Corresponding experimental groups were given either tap water or a solution of 1% NaCl and 5% glucose in tap water to drink. In rats fed with a diet free of PA and in addition treated with Ω-methyl-PA a severe disturbance of the corticoid balance developed within 6 weeks. The corticosterone production was depressed to about 11–16% of the control values. The adrenal cortex showed necrotic changes which either involved the whole parenchyma or were confined to the inner zones. In those animals in which a subcapsular region, in its extent corresponding to the zona glomerulosa, remained intact, an augmentation of the CRF-granules was observed. In those animals, however, in which the whole adrenal cortex was damaged, the amount of CRF-granules did not increase. Administration of the 1% NaCl containing drinking fluid did not influence the augmentation of the CRF granules, but had a protective effect on the development of necrotic changes in the zona glomerulosa of the adrenal cortex. The findings show that a functional relationship exists between the inner zones of the adrenal cortex and the CRF-granules in the median eminence.
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  • 70
    ISSN: 1432-0568
    Keywords: Neurohypophysis ; Neuro-vascular contacts ; Neuro-glial synaptoid contacts ; Dehydration ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The posterior lobe of the hypophysis consists of neurosecretory nerve fibres and glial cells, both abutting on the perivascular space of sinusoidal capillaries. Nerve fiberes and glial cells are connected with each other by a high number of synaptoid contacts. Several ultrastructural changes following dehydration have been described by other authors. This study presents the data of some morphometric investigations on normal and dehydrated rats. The relative extent of neuro-vascular contacts is not contstant; it increases significantly from 52 (±2.8)% in normal rats to 67(±1.2)% in rats with a dehydration time of 3 days. Correspondingly the extent of glio-vascular contacts is diminished. In addition, water-deprived animals show a clear increase in the number of neuro-glial synaptoid contacts with 3.1 (±0.4) per square unit nervous tissue compared to 2.1 (±0.3) per Square unit in untreated controls. These results indicate a dynamic motility of neuronal and glial elements depending on functional conditions, as was found for the external layer of the median eminence. Furthermore there seems to be a relationship between secretory activity and the number of neuroglial synaptoid contacts.
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  • 71
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    Acta neuropathologica 28 (1974), S. 25-35 
    ISSN: 1432-0533
    Keywords: Chronic Lead Intoxication ; Rat ; Ultrastructure ; Microglia ; Pericytes ; Monocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Wistar rats of both sexes and the same litter were exposed to chronic lead intoxication from birth untill sacrifice 9 months later. Lead was administered as 0.4% solution of lead nitrate in drinking water. Samples from the parietal brain cortex were examined electron microscopically following intracardiac perfusion with paraformaldehyde-glutaraldehyde solution. Similar changes were observed in the microglial cells and the vascular pericytes whereas all the other tissue elements appeared intact. Both cell types hypertrophied, the microglia assumed characteristic spindle or rod shape, the cell organelles increased, the microglial endoplasmic reticulum widened strongly and a large number of lipid inclusions appeared. The latter consisted of large lipid droplets of varying size and shape, containing multiple zones of low density, and a dense component with a coarse granular structure. The similarity in the response of both cell entities to the lesion as well as some probable functions of microglial cells and their relationship to vascular pericytes are discussed.
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  • 72
    ISSN: 1432-0533
    Keywords: Allergic Encephalomyelitis ; Organ Culture ; Brain ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Experimental allergic encephalomyelitis (EAE) developed in 15 of 30 rats injected with a mixture of Freund's adjuvant and homogenized guinea pig brain, and killed after 6–29 days. The incidence and severity of the disease increased with time after inoculation and in 2 animals involvement of the epiphysis, not previously reported in EAE, was detected. Toxic effects on cells in cultured adult rat cerebellar cortical tissue were produced by exposure for 24 h to the sera of rats killed 12–29 days after inoculation either with the antigenic suspension or with adjuvant alone. Severe toxicity to axons (widespread fragmentation) was produced only by the sera of animals injected with antigenic inocula and killed 17–29 days later. Severe axonal toxicity was not, however, correlated with the presence of EAE in the rats from which the sera were taken. It was not possible to assess myelinotoxic effects in the system used. It is suggested that the organ culture technique may detect the presence in the sera of inoculated animals of toxic principles which, owing to the blood-brain barrier, do not normally contribute to the pathogenesis of EAE.
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  • 73
    ISSN: 1432-0533
    Keywords: Cholesterol Inhibitors ; Cerebrum ; Neuronal Inclusions ; Oligodendroglial Degeneration ; Rat ; Abnormal Sterols
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Wistar strain of rats received daily intraperitoneal or oral administration of Triparanol, 250 mg per kg of body weight or 20,25-diazacholesterol either 30 mg or 60 mg per kg of body weight starting at the age of 5 days old. Prominent intracytoplasmic osmiophilic inclusions identical to those found in the rats treated with AY9944 (Suzukiet al., 1973) and degeneration of myelin sheaths and oligodendroglia were seen in the myelinating white matter of rats sacrificed after 3, 6, and 9 injections of Triparanol. In diazacholesterol-treated animals, a few identical inclusions were seen in the cortical neurons but only slight changes were seen in oligodendroglia. Biochemical analysis of the brains of the rats receiving Triparanol revealed a large accumulation ofΔ 7,24-cholestadiene-3β-ol and lesser amounts of desmosterol. The brains of the animals treated with diazacholesterol revealed massive accumulation of desmosterol and a minor sterol component, probablyΔ 5,7,24-cholestatriene-3β-ol. Since AY9944, which results in a massive accumulation of 7 dehydrocholesterol (Δ 5,7-cholestadiene-3β-ol) and two other sterols,Δ 7,24-cholestadiene-3β-ol andΔ 5,7,24-cholestatriene-3β-ol, will produce identical neuropathological lesions to those seen in Triparanol treated animals, and since the lesion produced in diazacholesterol treated animals was very slight, there appears to be a correlation between the presence of sterols with a double bond at the 7-position and neuropathological lesions in young rats.
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  • 74
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    Acta neuropathologica 27 (1974), S. 25-32 
    ISSN: 1432-0533
    Keywords: Experimental CNS Tumours ; Nitrosomethylurea ; Ethylnitrosourea ; Primary Cultures ; Tumour Classification ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary By means of the explant technique a series of primary tumours induced by methylnitrosourea (MNU) or ethylnitrosourea (ENU) in the brain of rats were cultured in vitro. The morphology of isomorphic oligodendrogliomas, astrocytomas, glioblastomas and sarcomas under in vitro conditions is described. All these neoplasias show a very distinct morphological picture and growth behaviour, thus permitting their classification. Most of the tumours tend to anaplastic changes during longer cultivation, but in some cases, preferably in well differentiated gliomas, the cytological properties are maintained even during longterm cultivation. The role of anaplasia and intermingling of different neoplastic cell types in experimental tumours are discussed.
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  • 75
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    Experimental brain research 20 (1974), S. 181-192 
    ISSN: 1432-1106
    Keywords: Locus ceruleus ; Cerulo-cortical tract ; Ascending reticular fiber ; Rat ; Fink-Heimer method
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In order to demonstrate the ascending projection from the locus ceruleus by degeneration silver method, the nucleus was destroyed unilaterally in rats and the brains were stained by a modified Fink-Heimer method following various survival times. Additional experiments included the bilateral destruction of the locus ceruleus and the administration of 6-OH-DOPA. For the demonstration of degenerated terminals in the cerebral cortex it is essential to choose an optimal survival time of 4 or 5 days, keep the time of fixation below 1 week, and perform treatments with permanganate and with silver at 37°C. The trajectory and distribution of the cerulo-cortical tract as revealed by the silver degeneration methods is in agreement with the results of the histofluorescence method, with some minor differences. The ascending fibers run through Forel's tegmental fascicle, turn rostro-ventrally to the subthalamus, enter and cross the internal capsule, pass through the ventral part of the caudate-putamen and distribute to the entire cerebral cortex. The tract is mainly ipsilateral, though some fibers are crossing.
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  • 76
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    Experimental brain research 21 (1974), S. 107-112 
    ISSN: 1432-1106
    Keywords: Preoptic units ; Thermosensitivity ; Mean firing rate ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Mean firing rates (per 10 sec) of preoptic neurons of the rat were recorded at normal temperature and after central warming and cooling. Thermosensitivity was determined according to the reactions of the mean firing rate. In compatibility with results from other animals we obtained the following percentages (52 neurons): 23% warm-sensitive, 13% cold-sensitive, 64% non-thermosensitive neurons. However, it turned out that a lot of interesting special effects are not taken into account, using exclusively the criterion “increasing/decreasing/constant mean firing rate”. Particularly we observed long lasting adaption processes and stationary non-linear effects as well as striking oscillations which were dependent on the thermal stimuli, while the mean interval value remained constant.
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  • 77
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    Langenbeck's archives of surgery 336 (1974), S. 15-23 
    ISSN: 1435-2451
    Keywords: Rat ; Splenectomy ; Gastric Ulceration ; Increase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung An Ratten wurde der Einfluß von Splenektomie auf Magensaftsekretion und Ulcusentstehung untersucht. Sowohl nach “restraint-stress” als auch Pylorusligatur wiesen die splenektomierten Tiere eine ausgeprägte Steigerung der Ulcuszahl und -größe gegenüber den Kontrolltieren auf. In der Magensaftanalyse waren dagegen die Werte der splenektomierten Tiere gegenüber den scheinoperierten nur geringgradig gesteigert. — Als mögliche Ursache der vermehrten Ulcusanfälligkeit nach Splenektomie wurde eine Veränderung lokaler, nicht säuresekretorischer Faktoren der Magenwand diskutiert.
    Notes: Summary In Splenectomiced rats incidence of gastric ulceration was compaired with control groups. Restraint stress and ligation of pylorus was used as model. Splenectomiced rats do show an higher incidence in both models. Both frequency and extension of gastric ulcer were accumulated significantly. Analysis of gastric secretion was only unessentially raised in comparisom to control-groups. Change of protective factors of stomach as possible reason is discussed.
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  • 78
    ISSN: 1432-0738
    Keywords: Alcohol, Ethyl ; Absorption ; Elimination ; Alcohol Oxidoreductases ; Hepatitis, Toxic ; Transaminases ; Glutamate Dehydrogenase ; Guinea Pig ; Rat ; Äthylalkohol ; Resorption ; Elimination ; Alkoholdehydrogenase ; Hepatotoxicität ; Transaminasen ; Glutamatdehydrogenase ; Meerschweinchen ; Ratte
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Die maximalen Blutalkoholkonzentrationen nach oraler Gabe von 6,4 g/kg Äthanol in Form einer 40%igen Lösung (v/v) betrugen bei nicht nüchternen Meerschweinchen 6,8±0,3 mg/ml, bei nicht nüchternen Ratten dagegen nur 2,1±0,2 mg/ml. An nüchternen Tieren führte eine orale Alkoholbelastung von 4,8 g/kg zu maximalen Blutalkoholspiegeln von 6,3±0,2 mg/ml bei den Meerschweinchen und 3,7±0,3 mg/ml bei den Ratten. Intravenös injizierter Alkohol (1 g/kg) wurde demgegenüber von beiden Species mit der gleichen Geschwindigkeit eliminiert (275 mg/kg · Std), und die auf das Körpergewicht bezogene ADH-Aktivität der Leber war bei den Meerschweinchen um 20% größer als bei den Ratten. Die Resorption von Äthanol erfolgt somit bei Ratten erheblich langsamer als bei Meerschweinchen. Dies dürfte darauf beruhen, daß konzentrierte Alkohollösungen die Magenentleerung der Ratte stark verzögern. Niedriger konzentrierte Alkohollösungen werden von der Ratte schneller resorbiert; jedoch waren auch nach Gabe von 10%igem Alkohol die maximalen Blutalkoholspiegel bei Ratten noch um 36% niedriger als bei Meerschweinchen. Bei den Meerschweinchen waren nach oraler Gabe von 4,8 bzw. 6,4 g/kg Äthanol die Serumaktivitäten der GOT, GPT und GLDH erhöht; ein Anstieg der SGOT trat schon nach 1,6 g/kg Äthanol auf. Demgegenüber kam es bei Ratten nach 6,4 g pro kg Äthanol p.o. nur zu geringfügigen Aktivitätserhöhungen der Serumtransaminasen, während die Serumaktivität der GLDH unverändert blieb. Vacuolige Degeneration war das morphologische Substrat der durch Äthanol bei Meerschweinchen und Ratten ausgelösten Leberschädigung. Während diese Veränderung bei Meerschweinchen bereits nach einer Äthanoldosis von 1,6 g/kg auftrat, wurde sie bei Ratten erst nach 6,4 g/kg beobachtet. Schlußfolgerung: Das Meerschweinchen ist für Untersuchungen zur Toxicität von Äthanol besser geeignet als die Ratte.
    Notes: Abstract In fed guinea pigs, an oral dose of 6.4 g/kg of ethanol given as a 40% solution (v/v) produced a maximal blood alcohol level of 6.8±0.3 mg/ml, whereas in fed rats, blood alcohol levels after the same dose did not exceed 2.1±0.2 mg/ml. Maximal blood alcohol levels in fasted animals after an oral load of 4.8 g/kg of ethanol were 6.3±0.2 mg/ml in guinea pigs and 3.7±0.3 mg/ml for rats. However, i.v. injected ethanol (1 g/kg) was eliminated at the same rate in both species (275 mg per kg · h), and ADH activity of the liver related to body weight was by 20% greater in guinea pigs than in rats. Therefore, absorption of ethanol occurs at a much slower rate in rats than in guinea pigs. This is possibly due to the fact that high ethanol concentrations strongly delay emptying of the rat stomach. Lowering the ethanol concentration accelerates absorption rate in the rat. However, even after gavage of a 10% solution peak levels of blood alcohol were still lower by 36% in rats than in guinea pigs. In guinea pigs, increased serum activities of GOT, GPT, and GLDH occurred after an oral dose of 4.8 g/kg or 6.4 g/kg of ethanol, respectively. SGOT already increased after 1.6 g/kg of ethanol p.o. After 6.4 g/kg of ethanol given to rats serum transaminase levels increased only slightly, and GLDH activity not at all. Vacuolar degeneration was the morphological substrate of ethanol-induced liver damage in guinea pigs and rats. In guinea-pigs, it occurred already after 1.6 g/kg of ethanol, whereas in rats only after 6.4 g/kg. In conclusion, the guinea pig seems to be better suited for research on alcohol toxicity than the rat.
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    Research in experimental medicine 162 (1974), S. 313-321 
    ISSN: 1433-8580
    Keywords: Coprophagy ; Rat ; Calcium metabolism ; Bone morphology ; Immobilization ; Koprophagie ; Ratte ; Calciumstoffwechsel ; Knochenmorphologie ; Immobilisierung
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Wir untersuchten den Einfluß der Koprophagie auf den Calciumstoffwechsel der Ratte. 20 Versuchstiere wurden durch Einschnüren in einen Lederpanzer an der Koprophagie gehindert und mit 21 Kontrolltieren gleicher Futteraufnahme verglichen. Die Kinetik des Calciumstoffwechsels wurde unter Verwendung von45Ca als Tracer analysiert. Die radiochemischen Resultate wurden mit den histologischen Beobachtungen an den Epi-Metaphysen der Kniegelenke verglichen. Bei den Versuchstieren mit verhinderter Koprophagie fanden wir: 1. ein hochsignifikant niedrigeres Körpergewicht; 2. eine hochsignifikante Verkleinerung folgender Parameter des Calciumstoffwechsels: Compartmentgröße und Austauschrate zwischen ihnen, Calciumausscheidungsraten, Knochenan- und -abbau; 3. eine Verschmälerung der Wachstumsfuge, verkürzte und verschmälerte primäre Knochenbälkchen, verminderte sekundäre metaphysäre Spongiosa. Bei 4 Versuchstieren, die in Lederpanzern gehalten, denen jedoch die Koprophagie ermöglicht war, wurden gleichartige histologische Veränderungen wie bei verhinderter Koprophagie festgestellt. Es wird gefolgert, daß die Verhinderung der Koprophagie keinen meßbaren Einfluß auf die Parameter des Calciumstoffwechsels hat.
    Notes: Summary We investigated the influence of coprophagy on the calcium metabolism of the rat. 20 experimental animals were prevented from coprophagy by wrapping them in leather harnesses and compared with 21 controls on the same food intake. Kinetics of calcium metabolism were analysed using45Ca as tracer. The radiochemical results were compared with the histological observations in the epi-metaphyses of the knee joints. In the experimental animals prevented from coprophagy we found: 1. a highly significant lower body weight; 2. a highly significant diminution of the following parameters of calcium metabolism: compartment sizes and exchange rate between them, calcium excretion rates, bone accretion and resorption; 3. a narrower epiphyseal growth cartilage, clearly shorter and narrower primary trabeculae, rarefied secondary metaphyseal trabeculae. Histological alterations identical to those observed with coprophagy prevented, were found in 4 animals kept in harnesses but with coprophagy allowed. It is concluded that prevention of coprophagy has no measurable influence on the parameters of calcium metabolism.
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    Research in experimental medicine 163 (1974), S. 39-45 
    ISSN: 1433-8580
    Keywords: D-penicillamine ; Acetazolamide ; Renal excretion ; Rat ; D-Penicillamin ; Acetazolamid ; Renale Exkretion ; Ratte
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Die renale Ausscheidung von D-Penicillamin läßt sich weder durch Probenecid noch durch N-Methylnicotinamid oder NH4Cl beeinflussen. Acetazolamid bewirkt eine erhöhte Retention von D-Penicillamin in Haut und Muskulatur und hemmt dessen renale Ausscheidung, hat jedoch keinen Effekt auf die Dekorporationswirksamkeit von D-Penicillamin bei60Co. Die möglichen Ursachen des Einflusses von Acetazolamid auf die Verteilung und Exkretion von D-Penicillamin werden diskutiert.
    Notes: Summary The renal excretion of D-penicillamine is not influenced by probenecid, N-methylnicotinamide, and NH4Cl. Acetazolamide brings about an increased retention of D-penicillamine in skin and muscles and lowers its urinary excretion, but does not exhibit any influence on the efficacy of D-penicillamine in removing internally deposited60Co. The possible causes for the action of acetazolamide on the distribution and excretion of D-penicillamine are discussed.
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    Research in experimental medicine 163 (1974), S. 289-298 
    ISSN: 1433-8580
    Keywords: Gastrinpentapeptide ; Vagotomy ; Acid secretion ; Perfusion test ; Rat ; Gastrinpentapeptid ; Vagotomie ; Säuresekretion ; Perfusionsversuch ; Ratte
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Bei männlichen Wistarratten wurde eine trunkuläre beiderseitige Vagotomie — ergänzt durch eine Pyloroplastik — angelegt. 4 Wochen später erfolgte in Urethannarkose eine Perfusion des Magens mit 0,9%iger NaCl-Lösung in Anlehnung an die Versuchsanordnung von Ghosh. Die Vollständigkeit der Vagotomie bestätigte ein Hypoglykämietest. Im Abstand von 150 min erhielten die Tiere — in 6 Gruppen zu je 10 Ratten — 2 × 50, 100, 150, 200, 250 oder 300 µg/kg KG Pentagastrin subcutan. Die statistisch ausgewerteten Ergebnisse lassen sich wie folgt zusammenfassen: 1. Die nach dem Abklingen der Wirkung der ersten Pentagastrininjektion wiederholte Pentagastringabe in derselben Dosis ergab bei allen Dosierungen eine höhere Säuresekretion als nach der ersten Injektion. 2. Ein Maximum der sezernierten Säuremenge wurde bei einer Dosis von 100 µg/kg KG erreicht. Bei höherer Dosierung des Pentagastrins nahm die Menge der sezernierten Säure signifikant ab.
    Notes: Summary Male Wistar rats were subjected to a complete bilateral vagotomy and a pyloroplasty. 4 weeks later followed in urethane anesthesia a continuous perfusion of the stomach with 0.9% saline according to the rat preparation of Ghosh. The completeness of the gastric vagotomy was confirmed by a postoperative insulin test. In an interval of 150 min the rats — in 6 groups of 10 rats each — were two times injected pentagastrin subcutaneously in dose rates of 50, 100, 150, 250 or 300 µg/kg body weight. The statistical confirmed results can be summarized as followed: 1. The second injection of pentagastrin — 150 min after the first — in the same dose produced a significantly higher gastric acid secretion in the rat all dose rates in comparison to the first injection. 2. The maximal gastric acid secretion was produced by a dose rate of 100 µg/kg body weight of pentagastrin. At higher dose rates of pentagastrin there was a significant reduction of gastric acid secretion.
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    Research in experimental medicine 164 (1974), S. 19-33 
    ISSN: 1433-8580
    Keywords: Kidney ; Rat ; Ultrastructure ; Proximal tubule degeneration ; Heparinoid ; Niere ; Ratte ; Ultrastruktur ; Proximale Tubulusdegeneration ; Heparinoid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung 24 Std nach i.v. Injektion von 100 mg/kg eines Pentosanschwefelsäureesters (SP 54) sind in der Nierenrinde von Ratten schwere degenerative Veränderungen der proximalen Tubuluszellen zu beobachten. Das Tubulusepithel ist flachkubisch umgewandelt, das Tubuluslumen ist angefüllt mit ausgestoßenen Mitochondrien und anderen Zelltrümmern. Am stärksten betroffen ist die Pars contorta des proximalen Tubulus. Weniger stark veränderte Tubuluszellen sind angefüllt mit Cytosomen, die eine spezifische Feinstruktur haben oder gehäuft gegenüber Kontrollen Cytoplasmaprotrusionen in das Tubuluslumen aufweisen. Die akute Tubulusdegeneration ist ein spezifischer Effekt von SP 54. Heparin bewirkt nur eine leichte Schwellung des Tubulusepithels, die häufiger auftritt als bei Kontrolltieren.
    Notes: Summary 24 hrs after the intravenous injection of 100 mg/kg of a Pentosansulfuricacidester (SP 54) severe degenerative alterations are observed in the proximal tubular cells in rat kidney cortex. The tubular epithelium has changed to a single layer of elongated cubic cells. The tubular lumen is filled with cellular debris and extruded mitochondria. The greatest change is seen in the pars contorta of the proximal tubule. Less degenerated tubular cells have a great number of cytosomes with a specific substructure or have cytoplasmatic protrusions into the tubular lumen. This acute tubular degeneration is a specific event after the administration of SP 54 and is not seen after an equimolar dosis of Heparin. Heparin induces only a slight swelling of the tubular epithelium, more frequent seen as in the control animals.
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    Research in experimental medicine 163 (1974), S. 341-349 
    ISSN: 1433-8580
    Keywords: Experimental uremic syndrome ; Rat ; 5/6 reduction of renal parenchyma ; Serum- and urine analysis ; Secondary hyperparathyroidism ; Experimentelles urämisches Syndrom ; Ratte ; 5/6-Reduktion des Nierenparenchyms ; Serum- und Urinanalyse ; Sekundärer Hyperparathyreoidismus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Durch eine 5/6-Nierenparenchymreduktion wurde an Ratten ein chronisches, durch bilaterale Nephrektomie ein akutes urämisches Syndrom erzeugt. Beim chronischen urämischen Syndrom erwiesen sich in der Serumanalyse die Konzentrationen des Harnstoffstickstoffs und des Kreatinins als wesentlich erhöht. Darüber hinaus bestanden alle chemischen Zeichen eines sekundären Hyperparathyreoidismus. Die Tiere litten außerdem an einer schweren Poly-, Protein- und Albuminurie. Überraschenderweise war aber der Spiegel des totalen Serumproteins gegenüber den Kontrolltieren erhöht. Das experimentelle chronische urämische Syndrom stellt eine extreme Adaptation der regulatorischen Aktivität des Nierenrestparenchyms und des ganzen Organismus dar. Beim akuten, durch bilaterale Nephrektomie erzeugten urämischen Syndrom besteht dagegen ein schweres Versagen der Regulation des Wasser- und Elektrolytstoffwechsels, welches innert 50–60 Std zum Tode der Versuchstiere führt.
    Notes: Summary A chronic uremic syndrome was induced by 5/6 nephrectomy and an acute uremic syndrome by bilateral nephrectomy in rats. In the chronic uremic syndrome serum and urine analysis revealed a highly increased serum level of BUN and creatinine. Furthermore, all chemical signs typical of secondary hyperparathyroidism were present. The animals suffered from severe polyuria, protein- and albuminuria but, surprisingly, the total serum protein was increased. The experimental chronic uremic syndrome is, in essence, a syndrome of “extreme adaptation” of the regulatory activity of remnant renal parenchyma and of the whole body. In contrast, the acute uremic syndrome induced by bilateral nephrectomy is a severe disorder of water and electrolyte metabolism resulting in death of the experimental animals after 50–60 hrs.
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    Pflügers Archiv 352 (1974), S. 121-133 
    ISSN: 1432-2013
    Keywords: Urate ; Protein Interaction ; Uptake by Erythrocytes ; Renal Reabsorption ; Man ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Interaction of urate with human and rat plasma was studied by a dialysis technique at different temperatures. At 4° C a certain fraction of urate is bound to proteins. However, this fraction diminishes with increasing temperature and at 37° C only some 7–8% (in man) and 2% (in rat) interact with proteins. The finding that urate is almost completely filtered in the glomerulus is discussed. In body areas exposed to low temperatures protein binding of urate may be of importance. Urate uptake by erythrocytes is characterized by two components: a fast component equilibrating almost immediately at about 7% in man and 17% in rat and a slow component reaching equilibrium after 60 min, at 28% and 36%, respectively. The process is described by a mathematical formula. Lowering of the temperature mainly diminishes uptake by the slow component withQ 10-values ranging between 1.5 and 4.0. In the observed range of concentrations the uptake process does not saturate. The results at lower pH-values suggest that it is unionized uric acid which is transported by the slow component. Application of the data to kidney medulla supports the hypothesis that erythrocytes and, probably, to a lesser extent plasma proteins serve as vehicles for urate reabsorption in the countercurrent system. Such a temporary interaction enables uric acid to escape recirculation and to leave the kidney medulla.
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    Pflügers Archiv 352 (1974), S. 115-120 
    ISSN: 1432-2013
    Keywords: Urate ; Reabsorption ; Loop of Henle ; Micropuncture ; Microperfusion ; Microinjection ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Reabsorption rates for urate in the loops of Henle were measured in superficial nephrons in the rat 1. under conditions of free flow, 2. using microperfusion and 3. by a microinjection technique. 1. Under conditions of free flow distally measured TF/PUA/TF/PIn-values varied between 0.51 and 0.38 in antidiuretic rats, depending on TF/PIn (UA = both uric acid and urate, In = inulin, TF/P = concentration in tubular fluid to plasma concentration). The corresponding values in samples from end-proximal tubules were 1.06 and in urine 0.19 (U/PUA/U/PIn). 2. In microperfusion experiments of Henle loops early distal recoveries of 2-C14 urate varied between 57 and 86%, depending on the flow rates (10–40 nl/min). 3. In microinjection experiments C14 recovery in urine was about 85% when tracer solution was microinjected into endproximal tubules. From these results we conclude: 1. The main site of urate reabsorption is located in the loops of Henle. 2. This reabsorption is highly dependent on flow rates. Increase of flow rate through Henle's loop decreases urate reabsorption.
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    Calcified tissue international 14 (1974), S. 283-289 
    ISSN: 1432-0827
    Keywords: Sodium fluoride ; Osteoporosis ; Bone ; Strength ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Physics
    Description / Table of Contents: Résumé L'utilisation thérapeutique de fluorure de sodium a été recommandée dans le traitement de diverses maladies osseuses ostéopéniques. Cet emploi est basé principalement sur les effects ostéosclérotiques bien connus du fluorure de sodium, mais on connait mal son effet sur la force de résistance osseuse. L'influence de diverses concentrations de fluorure de sodium sur la force de résistance osseuse de jeunes rats soumis à des régimes riches et pauvres en calcium a été étudiée. L'administration de fluorure de sodium augmente le diamètre osseux, indiquant une stimulation de la formation de l'os périosté, mais la force de résistance osseuse est réduite ou non modifiée par l'ingestion de fluor.
    Abstract: Zusammenfassung Die therapeutische Verwendung von Natriumfluorid ist für eine Anzahl von Knochenmangel-Krankheiten empfohlen worden. Die Empfehlungen basieren hauptsächlich auf den bekannten osteosklerotischen Wirkungen von Natriumfluorid; über dessen Effekt auf die Knochenstärke ist wenig bekannt. In dieser Arbeit wurde der Einfluß verschiedener Konzentrationen von Natriumfluorid auf die Knochenstärken von wachsenden Ratten mit hoher und niederer Calciumeinnahme untersucht. Die Verabreichung von Natriumfluorid erhöhte den Knochendurchmesser, was auf eine Stimulierung der Periostbildung hinwies, die Knochenstärke wurde jedoch durch Fluorideinnahme herabgesetzt oder nicht beeinflußt.
    Notes: Abstract The therapeutic use of sodium fluoride has been recommended in a variety of osteopenic bone diseases. The recommendations are based mainly on the known osteosclerotic effects of sodium fluoride and little information is available as to its effect on bone strength. The influence of various concentrations of sodium fluoride on bone strength in growing rats on high and low calcium diets was studied. The administration of sodium fluoride increased bone diameter, indicating stimulation of periosteal bone formation, but bone strength was reduced or not affected by fluoride ingestion.
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    Naunyn-Schmiedeberg's archives of pharmacology 281 (1974), S. 197-217 
    ISSN: 1432-1912
    Keywords: Intestinal Absorption ; Acidic Drugs ; Benzoic Acid ; Salicylic Acid ; Solvent Drag ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Jejunal loops of anaesthetized rats were perfused with hypotonic, isotonic and hypertonic buffered solutions containing 14C-labelled benzoic acid and salicylic acid at pH 6.2 and 2.2. The blood flow of the loop was maintained at an intermediate rate (0.78–0.97 ml min−1 g−1). The water net flux was determined by polyethylene glycol as non-absorbable marker and amounted up to +31 or-27 μl min−1 g−1. 2. A positive water net flux (leaving the gut lumen) increased the appearance rate of benzoic acid and salicylic acid in the intestinal venous blood by maximally 47 and 41%, a negative water net flux (entering the gut lumen) diminished the appearance rate by 28 and 37%. 3. The experimental data were analysed by means of a kinetic model. The parameters of the model were the epithelial permeability kF D , the serosal permeability k S F S and the sieving coefficient Φ=1−σ. The epithelial permeability was 0.115 and 0.107 for benzoic acid and salicylic acid at pH 6.2 and increased to 0.163 and 0.185 ml min−1 g−1 at pH 2.2. The serosal permeability was assumed to be identical for neutral and acidic pH and amounted to 0.046 and 0.112 ml min−1 g−1 indicating that a certain proportion of the absorbed drugs was transferred to the serosal side. The sieving coefficient was 2.92 and 2.31 at neutral pH and 3.79 and 3.56 at acidic pH. 4. The main resistance to the absorption of the two drugs is the epithelial membrane, since the effective blood flow and the unstirred layer are not ratelimiting. The high sieving coefficient for the two drugs is interpreted as indicating an interaction of drug and water molecules inside the lipid part of the cell membrane (which contains at least 30% water). The electric potential across the gut wall may contribute to the size of the sieving coefficient, if the drug molecules permeate also in the ionized form. 5. Using acidic perfusion solutions the epithelial permeability and the sieving coefficient were increased by the factor 1.3–1.5. This increase can be explained sufficiently by a facilitated entrance of the unionized drug molecules into the epithelial membrane.
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    Naunyn-Schmiedeberg's archives of pharmacology 285 (1974), S. 175-184 
    ISSN: 1432-1912
    Keywords: Fenfluramine ; Rat ; Guinea Pig ; Phospholipidosis, drug-induced ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary After administration of the anorectic drug fenfluramine (40 mg/kg per day) to rats (s. c. or i. p.) and guinea pigs (p.o.) over periods of 2 to 11 weeks, electron microscopic examination was performed on lungs, liver, lymphatic tissues and peripheral blood of both species, and on adrenal glands and ovaries of rats. In rats, fenfluramine caused the following alterations (listed according to the duration of treatment): Formation of abnormal lamellated inclusions in lymphocytes and plasma cells of lymphatic tissues, appearance of “foam cells” in lung alveoli; formation of abnormal lamellated inclusions in corpus luteum, lymphocytes of peripheral blood, and in adrenal cortex. In guinea pigs, the same alterations were found in lymphocytes of spleen and peripheral blood, in hepatocytes and in lung. The present observations support the concept of a generalized phospholipidosis induced by amphiphilic compounds. The potency of fenfluramine to induce a lipidosis is, however, considerably less pronounced than that previously demonstrated for the anorectic drug chlorphentermine. This difference is suggested to be due mainly to the lower degree of amphiphilia of fenfluramine.
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    Naunyn-Schmiedeberg's archives of pharmacology 282 (1974), S. 195-212 
    ISSN: 1432-1912
    Keywords: Intestinal Blood Flow ; Intestinal Absorption ; d-Galactose ; Phlorizine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Jejunal loops of anaesthetized rats were perfused with buffered solutions (pH 6.8) containing d-galactose in two concentrations: below (100 μM) and above (100 mM) blood sugar concentration. The blood flow rate, the appearance rate (in the intestinal venous blood) and the disappearance rate (from the intestinal lumen) were determined simultaneously, the accumulation in gut tissue at the end of the experiments. 2. At constant intermediate blood flow the appearance rate and disappearance rate decreased with time. A decrease of the blood flow rate from about 1.9 to about 0.3 ml min−1 g−1 diminished both the appearance and the disappearance rate. An increase of blood flow from about 0.3 to about 1.9 ml min−1 g−1 did not increase the absorption rates; even a slight decrease was observed. 3. In the presence of phlorizine (2 mM) the absorption rates and the tissue accumulation of galactose is reduced. At constant intermediate blood flow the appearance and disappearance rate increased with time. A decrease of the blood flow rate from about 1.8 to about 0.3 ml min−1 g−1 diminished the appearance rate. An increase of the blood flow rate from about 0.3 to about 1.8 ml min−1 g−1 caused an increase of the appearance rate in contrast to the experiments without phlorizine. Therefore, the different blood flow dependence of the intestinal absorption observed with actively transported substances can be attributed to their non-passive component.
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    Naunyn-Schmiedeberg's archives of pharmacology 281 (1974), S. 175-196 
    ISSN: 1432-1912
    Keywords: Intestinal Absorption ; Basic Drugs ; Amidopyrine ; Antipyrine ; Solvent Drag ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Jejunal loops of anaesthetized rats were perfused with hypotonic, isotonic and hypertonic buffered solutions containing 14C-labelled amidopyrine and antipyrine at neutral and at acidic pH. The blood flow of the loop was maintained at an intermediate rate (0.7–1.0 ml min−1g−1). The water net flux was determined by means of polyethylene glycol as non-absorbable marker and amounted up to ±30 μl min−1g−1. 2. A positive water net flux (directed towards the blood) increased the appearance rate of amidopyrine and antipyrine by maximally 43.8 and 49.2%, a negative water net flux (directed towards the gut lumen) diminished it by 38.8 and 35.0%. 3. The experimental data were analysed by means of a kinetic model with the water net flux as independent variable and the epithelial permeability kF D , the serosal permeability k S F S and the sieving coefficient Φ=1−σ as absorption parameters. For antipyrine independent of the pH-value of the perfusion solution kF D was 0.123, and, for amidopyrine at pH 7 and pH 3 kF D was 0.231 and 0.091, respectively. k S F S was zero indicating that in this experimental arrangement the transfer of drug molecules to the serosal side was negligible. The sieving coefficient Φ amounted to 2.30 for amidopyrine and 2.15 for antipyrine at neutral pH. At acidic pH it amounted to 0.50 for amidopyrine and 1.44 for antipyrine. The hydraulic permeability of water was identical at neutral and acidic pH. 4. The high sieving coefficient for the two drugs at neutral pH is interpreted as indicating that water and lipophilic drug molecules interact within the lipid part of the cell membrane. At acidic pH the ionized drug molecules appear to permeate the cell membrane preferentially across other (presumably more hydrophilic) areas.
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    Pflügers Archiv 350 (1974), S. 241-248 
    ISSN: 1432-2013
    Keywords: Cardiac Hypertrophy ; Diffusion Distance of Oxygen ; High Altitude ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In rats born and staying their whole life at a simulated altitude of 3500 m a severe cardiac hypertrophy develops which is most pronounced in the right ventricle. On histological sections muscle fiber and capillary densities were counted and the surfaces occupied by muscle fibers and capillaries in the slides were estimated. Mean muscle fiber diameter and half mean distance between capillaries (diffusion distance) were obtained in the heart ventricles and were compared with those of control animals. In both ventricles an increase of the mean muscle fiber diameter occurred (true hypertrophy), being more pronounced in the right ventricle. We cannot tell whether also hyperplasia of muscle fibers occurred or not. The diffusion distance in the left ventricle of rats exposed to hypoxia was about the same as in control animals but was shorter in the right ventricle. This indicates that the total number of capillaries is higher in both ventricles of rats born in the low pressure chamber (hyperplasia of the capillaries). The shortening of the diffusion distance in the right ventricle of rats born and living their whole life at simulated high altitude was on the average smaller than that of rats exposed to simulated high altitude later in life. The physiological importance of this observation is discussed.
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    Pflügers Archiv 351 (1974), S. 13-24 
    ISSN: 1432-2013
    Keywords: Hypothalamus ; Spike-Trains ; Correlogram/Periodogram ; Thermosensitivity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Stationary spike-trains of preoptic neurons of the rat were submitted to a correlation- and spectral-analysis at normal temperature and after central warming and cooling. Correlograms and periodograms were computed which enable the elimination of stochastic signal components and the identification of the relevant periodic components. About one half of the analysed neurons showed periodic correlograms. The following three classes may be distinguished: Neurons which showed correlograms with periodicities at each applied thermal state, at only one or two thermal states and those with no recognizable periodicities at all. Relations between periodicity and the thermosensitivity of the neurons are discussed.
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    Pflügers Archiv 351 (1974), S. 323-330 
    ISSN: 1432-2013
    Keywords: Uricase ; Urate ; Allantoin ; Liver ; Kidney ; Microperfusion ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. In vivo uricase activity was tested in rats by injection of 2-C14 urate and measurement of the total C14 activity and the fractional activities of allantoin, allantoic acid and urea in samples of blood and urine. In control animals, 5 min after the injection, 70% of the plasma tracer was already present in the form of allantoin. No allantoic acid and urea were produced. Intestinectomy had no measurable influence on uricase activity. On the other hand, hepatectomy or ligation of the hepatic artery combined with subtotal viscerectomy did abolish uricase activity almost completely. 2. Following microinjections into proximal tubules of Ringer solution containing 2-C14 urate, urine samples during early recovery mainly contained labelled urate, whereas in later samples the fraction of labelled allantoin increased. About 12 min after the microinjection the urine of both kidneys contained equal amounts of tracer mainly in the form of allantoin. 3. When segments of proximal tubules were perfused with an equilibrium solution containing tracer amounts of C 14 urate, no urate was metabolized during its passage through the proximal tubule. 4. C 14 urate was offered from the peritubular capillaries and samples of tubular fluid were analyzed, Again, all the tracer in the tubular fluid was in the form of urate, indicating that urate is not oxidized when it is transported across the tubular cell. It is concluded from these results that: 1. The rat kidney has no significant uricase activity. 2. Urate transport in the kidney is not influenced by this enzyme. 3. The degradation of urate to allantoin takes place at extrarenal sites, mainly in the liver.
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    Psychopharmacology 37 (1974), S. 91-100 
    ISSN: 1432-2072
    Keywords: Ethanol ; Brain Serotonin Turnover ; Tolerance ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In rats treated acutely and chronically with ethanol, brain serotonin (5-HT) turnover was determined by measuring in the same animals the rate of accumulation of 5-HT and the rate of decline of 5-hydroxyindoleacetic acid (5-HIAA) in the brain after administration of the MAO inhibitor pargyline-HCl. In the acute study, 5-HT turnover was not altered after a single 4 g/kg oral dose of ethanol. In two separate studies, it was shown that chronic administration of ethanol in the form of a liquid diet for 32 days also did not alter brain 5-HT turnover, even when the rats had developed a significant degree of tolerance to the motor-impairing effects of ethanol. These results suggest that tolerance to ethanol is unrelated to any change in brain 5-HT turnover.
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    Psychopharmacology 37 (1974), S. 249-254 
    ISSN: 1432-2072
    Keywords: Chlorpromazine ; Rat ; Social Interaction ; Exploration ; General Motor Activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract When two animals were placed in a hole-board the number of headdips made by each rat was twice the number made when tested alone, but was the same for pairs of drugged (2 mg/kg chlorpromazine) and undrugged rats, and for pairs where only one rat was drugged. This contrasts with the reduction of headdipping produced by chlorpromazine in single animals. However, chlorpromazine still reduced general motor activity, regardless of whether the partner was drugged or not. The activity of the undrugged rats was affected by the partner's state and was lower when the partner was drugged.
    Type of Medium: Electronic Resource
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  • 96
    Electronic Resource
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    Springer
    Psychopharmacology 39 (1974), S. 237-244 
    ISSN: 1432-2072
    Keywords: Antagonism ; Fixed Interval ; Scopolamine ; Physostigmine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The purpose of this research was to determine if 2 drugs, scopolamine and physostigmine which have opposite effects on cholinergic transmission also produce opposite effects on fixed-interval (FI) performance. Scopolamine and a wide range of doses of physostigmine were administered singly and concurrently to a number of rats responding on a FI 2 min schedule. Scopolamine produced a disruption in FI curvature which could be antagonized by physostigmine, but physostigmine by itself produced no consistent change.
    Type of Medium: Electronic Resource
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  • 97
    Electronic Resource
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    Springer
    Psychopharmacology 35 (1974), S. 341-352 
    ISSN: 1432-2072
    Keywords: 6-Hydroxydopa ; Rat ; Behaviour ; Biogenic Amines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The influence of 6-hydroxydopa (6-HDP) injected into the lateral ventricles of rat brain on the behaviour of animals was examined. The level of noradrenaline (NA), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in discrete areas of the brain was also measured. 6-HDP was injected in a dose of 100 or 150 Μg into both lateral ventricles, or in a dose of 200 Μg into the right lateral ventricle. Immediately after 6-HDP injection, circling movements, convulsions, aggressive behaviour, and Stereotypic activity were seen. These components of behaviour were most obvious during the first hour after injection of 6-HDP. During one month after 6-HDP administration the behaviour of rats did not differ significantly from the behaviour of control animals, only very subtle differences in behaviour being seen. The dose of 150 Μg of 6-HDP caused aphagia and loss of body weigth during the first 5 days after treatment. 6-HDP also caused hypothermia. 20 min after administration of 200 Μg of 6-HDP a decrease of the NA level but no changes in the 5-HT level in the brain cortex were seen. The same changes were observed 1 month after 6-HDP treatment. The dose of 150 Μg of 6-HDP decreased the NA level in the brain cortex, cerebellum, mesencephalon and brain stem 5 days after treatment. 5-HT content was not changed and the 5-HIAA level was increased in the same brain areas. The dose of 100 Μg of 6-HDP, 2 weeks after the treatment decreased the content of NA in the brain cortex, cerebellum, hypothalamus and brain stem without changes in 5-HT content. 5-HIAA level was elevated only in the brain stem. It is concluded that 6-HDP is a long-acting potent depletor of NA in rat brain. There is a different sensitivity of brain areas to the depleting effect of 6-HDP. 6-HDP does not deplete the 5-HT content of discrete areas of brain but increases the level of 5-HIAA. 6-HDP causes distinct behavioural changes shortly after the treatment. It does not change the behaviour of rats between 1 and 30 days after its administration.
    Type of Medium: Electronic Resource
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  • 98
    ISSN: 1432-2072
    Keywords: LSD-25 ; UML ; 5-HT ; Brain ; Platelets ; Behaviour ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Factorial analysis of rat cerebral 5-HT values observed following intraperitoneal LSD-25 and UML (1-methyl-d-lysergic acid butanolamide) showed that the highly significant decrease induced by both drugs was independent of dose and that the effect of both drugs was the same. Increased platelet 5-HT values were also obtained with each drug. These findings suggest that the psychotomimetic effect of LSD-25 is not due to changes in cerebral 5-HT, since a relationship can probably be postulated between such an effect in man and the effect of LSD-25 on conditioned behaviour in the rat. It is also felt that the fact that these drugs decrease and increase cerebral and platelet values respectively may be of assistance in the interpretation of data relating to platelet 5-HT patterns in man under psychiatric conditions and during treatment with psychotropic drugs.
    Type of Medium: Electronic Resource
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  • 99
    ISSN: 1432-2072
    Keywords: Rat ; Chlordiazepoxide ; Diazepam ; Extinction ; Avoidance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In a one-way avoidance task with rats, injections of Librium (chlordiazepoxide) following avoidance acquisition resulted in prolonged resistance-to-extinction of the avoidance response. This effect occurred regardless of whether the rats had had prior experience with Librium or whether they were naive with respect to the drug. The same results were found with the same task when low doses of Valium were used. However, at a higher dosage an “extreme reaction” of either no responding or a high number of responses to extinction occurred in the naive animals. The Librium and Valium effects were compared to similar effects obtained using ethanol and hashish resin. These results indicate that the novelty hypothesis as originally stated by Amit and Baum cannot be supported because experience with the drugs prior to avoidance training did not attenuate the drug effect on avoidance.
    Type of Medium: Electronic Resource
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  • 100
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    Electronic Resource
    Springer
    Psychopharmacology 40 (1974), S. 91-99 
    ISSN: 1432-2072
    Keywords: Lithium ; Social Behaviour ; Sex ; Novelty ; Photographs ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Effects of lithium chloride on the social behaviour of male and female rats were measured in unfamiliar and familiar test situations using a photographic technique. Lithium-treated females showed an increase in body contact and a decrease in social distances in comparison with saline-treated controls in both test conditions. Males administered lithium showed increased corner occupancies in the novel test setting while in the familiar test they showed decreased body contact and increased average group social distance in comparison with the saline condition. Further tests in an exploration box confirmed that lithium decreased the general environmental responsiveness of male rats. The results are discussed with reference to the anti-aggressive effect of lithium.
    Type of Medium: Electronic Resource
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